Compositions and methods for coating medical implants

ABSTRACT

Medical implants are provided which release an anthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea, and/or platinum complex, thereby inhibiting or reducing the incidence of infection associated with the implant.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/447,309, filed May 27, 2003, which claims the benefit under 35 U.S.C.§ 119(e) of U.S. Provisional Patent Application No. 60/383,419, filedMay 24, 2002, which applications are incorporated herein by reference intheir entireties.

BACKGROUND

1. Technical Field

The present invention relates generally to pharmaceutical compositions,methods, and devices, and more specifically, to compositions and methodswhich reduce the likelihood of an infection associated with a medicalimplant.

2. Description of the Related Art

Infections associated with medical implants represent a major healthcareproblem. For example, 5% of patients admitted to an acute care facilitydevelop a hospital acquired infection. Hospital acquired infections(nosocomial infections) are the 11^(th) leading cause of death in the USand cost over $2 billion annually. Nosocomial infections directly cause19,000 deaths per year in the US and contribute to over 58,000 others.

The four most common causes of nosocomial infections are: urinary tractinfection (28%); surgical site infection (19%); respiratory tractinfection (17%); and bloodstream infection (16% and rising). Asignificant percentage of these infections are related to bacterialcolonization of implanted medical implants such as Foley catheters(urinary tract infections); surgical drains, meshes, sutures, artificialjoints, vascular grafts (wound infections); endotracheal andtracheostomy tubes (respiratory tract infection); and vascular infusioncatheters (bloodstream infections). Although any infectious agent caninfect medical implant, Staphylococci (S. aureus, S. epidermidis, S.pyogenes), Enterococci (E. coli), Gram Negative Aerobic Bacilli, andPseudomonas aeruginosa are common causes. Once a medical implant becomescolonized by bacteria, it must frequently be replaced resulting inincreased morbidity for the patient and increased cost to the healthcaresystem. Often the infected device serves as a source for a disseminatedinfection which can lead to significant morbidity or even death.

In an attempt to combat this important clinical problem, devices havebeen coated with antimicrobial drugs. Representative examples includeU.S. Pat. No. 5,520,664 (“Catheter Having a Long-Lasting AntimicrobialSurface Treatment”), U.S. Pat. No. 5,709,672 (“Silastic andPolymer-Based Catheters with Improved Antimicrobial/AntifungalProperties”), U.S. Pat. No. 6,361,526 (“Antimicrobial TympanostomyTubes”), U.S. Pat. No. 6,261,271 (“Anti-infective and antithrombogenicmedical articles and method for their preparation”), U.S. Pat. No.5,902,283 (“Antimicrobial impregnated catheters and other medicalimplants”) U.S. Pat. No. 5,624,704 (“Antimicrobial impregnated cathetersand other medical implants and method for impregnating catheters andother medical implants with an antimicrobial agent”) and U.S. Pat. No.5,709,672 (“Silastic and Polymer-Based Catheters with ImprovedAntimicrobial/Antifungal Properties”).

One difficulty with these devices, however, is that they can becomecolonized by bacteria resistant to the antibiotic coating. This canresult in at least two distinct clinical problems. First, the deviceserves as a source of infection in the body with the resultingdevelopment of a local or disseminated infection. Secondly, if aninfection develops, it cannot be treated with the antibiotic(s) used inthe device coating. The development of antibiotic-resistant strains ofmicrobes remains a significant healthcare problem, not just for theinfected patient, but also for the healthcare institution in which itdevelops.

Thus, there is a need in the art for medical implants which have areduced likelihood of an associated infection. The present inventiondiscloses such devices (as well as compositions and methods for makingsuch devices) which reduce the likelihood of infections in medicalimplants, and further, provides other, related advantages.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the effect of palmitic acid on the release profile of5-fluorouracil from a polyurethane sample.

BRIEF SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compositions and methodsfor preventing, reducing or inhibiting the likelihood of infectionsassociated with medical implants. More specifically, within one aspectof the invention medical implants or devices are provided which releasea chemotherapeutic agent, wherein the chemotherapeutic agent reduces,inhibits, or prevents the growth or transmission of foreign organisms(e.g., bacteria, fungi, or viruses) which are on or are associated withthe medical device or implant. For example, within one aspect of theinvention medical implant or devices are provided which release ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. Within variousembodiments, the implant is coated in whole or in part with acomposition comprising an anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex.

Other aspects of the present invention provide methods for makingmedical implants, comprising adapting a medical implant (e.g., coatingthe implant) with an anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex. Within certain embodiments, the desired therapeutic agent iscoated on and/or released from the medical implant at a dosage and/orconcentration which is less than the typical dosage and/or concentrationof the agent when used in the treatment of cancer.

A wide variety of medical implants can be generated using the methodsprovided herein, including for example, catheters (e.g., vascular anddialysis catheters), heart valves, cardiac pacemakers, implantablecardioverter defibrillators, grafts (e.g., vascular grafts), ear, nose,or throat implants, urological implants, endotracheal or tracheostomytubes, CNS shunts, orthopedic implants, and ocular implants. Withincertain embodiments, the catheter (e.g., vascular and dialysiscatheters), heart valve, cardiac pacemaker, implantable cardioverterdefibrillator, graft (e.g., vascular grafts), ear, nose, or throatimplant, urological implant, endotracheal or tracheostomy tube, CNSshunt, orthopedic implant, or ocular implant releases a fluoropyrimide(e.g., 5-FU) at a dosage and/or concentration which is less than atypical dosage and/or concentration which is used for the treatment ofcancer.

Within further aspects of the invention, there is provided a catheterwhich releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, thecatheter releases a fluoropyrimidine and in still another embodiment thefluoropyrimidine is 5-FU. In other embodiments, the catheter furthercomprises a polymer wherein the agent is released from a polymer on thecatheter. In certain embodiments, the catheter has a polymer that ispolyurethane or poly(lactide-co-glycolide) (PLG). In relatedembodiments, the catheter is a vascular catheter or a dialysis catheter.In still other embodiments, the catheter relaeases an agent that ispresent on the catheter at a concentration which is less than thetypical dosage and/or concentration that is used in the treatment ofcancer.

Within further aspects of the invention, there is provided a heart valvewhich releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, theheart valve releases a fluoropyrimidine and in still another embodimentthe fluoropyrimidine is 5-FU. In other embodiments, the heart valvefurther comprises a polymer wherein the agent is released from a polymeron the heart valve. In certain embodiments, the heart valve has apolymer that is polyurethane or PLG. In related embodiments, the heartvalve is a prosthetic heart valve. In still other embodiments, the heartvalve relaeases an agent that is present on the heart valve at aconcentration which is less than the typical dosage and/or concentrationthat is used in the treatment of cancer.

Within further aspects of the invention, there is provided a cardiacpacemaker which releases an agent selected from the group consisting ofan anthracycline, fluoropyrimidine, folic acid antagonist,podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In oneembodiment, the cardiac pacemaker releases a fluoropyrimidine and instill another embodiment the fluoropyrimidine is 5-FU. In otherembodiments, the cardiac pacemaker further comprises a polymer whereinthe agent is released from a polymer on the cardiac pacemaker. Incertain embodiments, the cardiac pacemaker has a polymer that ispolyurethane or PLG. In still other embodiments, the cardiac pacemakerrelaeases an agent that is present on the cardiac pacemaker at aconcentration which is less than the typical dosage and/or concentrationthat is used in the treatment of cancer.

Within further aspects of the invention, there is provided a implantablecardioverter defibrillator which releases an agent selected from thegroup consisting of an anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex. In one embodiment, the implantable cardioverter defibrillatorreleases a fluoropyrimidine and in still another embodiment thefluoropyrimidine is 5-FU. In other embodiments, the implantablecardioverter defibrillator further comprises a polymer wherein the agentis released from a polymer on the implantable cardioverterdefibrillator. In certain embodiments, the implantable cardioverterdefibrillator has a polymer that is polyurethane or PLG. In still otherembodiments, the implantable cardioverter defibrillator relaeases anagent that is present on the implantable cardioverter defibrillator at aconcentration which is less than the typical dosage and/or concentrationthat is used in the treatment of cancer.

Within further aspects of the invention, there is provided a graft whichreleases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, thegraft releases a fluoropyrimidine and in still another embodiment thefluoropyrimidine is 5-FU. In other embodiments, the graft furthercomprises a polymer wherein the agent is released from a polymer on thegraft. In certain embodiments, the graft has a polymer that ispolyurethane or PLG. In related embodiments, the graft is a vasculargraft or a hemodialysis access graft. In still other embodiments, thegraft relaeases an agent that is present on the graft at a concentrationwhich is less than the typical dosage and/or concentration that is usedin the treatment of cancer.

Within further aspects of the invention, there is provided a ear, nose,or throat implant which releases an agent selected from the groupconsisting of an anthracycline, fluoropyrimidine, folic acid antagonist,podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In oneembodiment, the ear, nose, or throat implant releases a fluoropyrimidineand in still another embodiment the fluoropyrimidine is 5-FU. In otherembodiments, the ear, nose, or throat implant further comprises apolymer wherein the agent is released from a polymer on the ear, nose,or throat implant. In certain embodiments, the ear, nose, or throatimplant has a polymer that is polyurethane or PLG. In relatedembodiments, the ear, nose, or throat implant is a tympanostomy tube ora sinus stent. In still other embodiments, the ear, nose, or throatimplant relaeases an agent that is present on the ear, nose, or throatimplant at a concentration which is less than the typical dosage and/orconcentration that is used in the treatment of cancer.

Within further aspects of the invention, there is provided a urologicalimplant which releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, theurological implant releases a fluoropyrimidine and in still anotherembodiment the fluoropyrimidine is 5-FU. In other embodiments, theurological implant further comprises a polymer wherein the agent isreleased from a polymer on the urological implant. In certainembodiments, the urological implant has a polymer that is polyurethaneor PLG. In related embodiments, the urological implant is a urinarycatheter, ureteral stent, urethral stent, bladder sphincter, or penileimplant. In still other embodiments, the urological implant relaeases anagent that is present on the urological implant at a concentration whichis less than the typical dosage and/or concentration that is used in thetreatment of cancer.

Within further aspects of the invention, there is provided aendotracheal or tracheostomy tube which releases an agent selected fromthe group consisting of an anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex. In one embodiment, the endotracheal or tracheostomy tubereleases a fluoropyrimidine and in still another embodiment thefluoropyrimidine is 5-FU. In other embodiments, the endotracheal ortracheostomy tube further comprises a polymer wherein the agent isreleased from a polymer on the endotracheal or tracheostomy tube. Incertain embodiments, the endotracheal or tracheostomy tube has a polymerthat is polyurethane or PLG. In still other embodiments, theendotracheal or tracheostomy tube relaeases an agent that is present onthe endotracheal or tracheostomy tube at a concentration which is lessthan the typical dosage and/or concentration that is used in thetreatment of cancer.

Within further aspects of the invention, there is provided a CNS shuntwhich releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, theCNS shunt releases a fluoropyrimidine and in still another embodimentthe fluoropyrimidine is 5-FU. In other embodiments, the CNS shuntfurther comprises a polymer wherein the agent is released from a polymeron the CNS shunt. In certain embodiments, the CNS shunt has a polymerthat is polyurethane or PLG. In related embodiments, the CNS shunt is aventriculopleural shunt, a VA shunt, or a VP shunt. In still otherembodiments, the CNS shunt relaeases an agent that is present on the CNSshunt at a concentration which is less than the typical dosage and/orconcentration that is used in the treatment of cancer.

Within further aspects of the invention, there is provided a orthopedicimplant which releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, theorthopedic implant releases a fluoropyrimidine and in still anotherembodiment the fluoropyrimidine is 5-FU. In other embodiments, theorthopedic implant further comprises a polymer wherein the agent isreleased from a polymer on the orthopedic implant. In certainembodiments, the orthopedic implant has a polymer that is polyurethaneor PLG. In related embodiments, the orthopedic implant is a prostheticjoint or fixation device. In still other embodiments, the orthopedicimplant relaeases an agent that is present on the orthopedic implant ata concentration which is less than the typical dosage and/orconcentration that is used in the treatment of cancer.

Within further aspects of the invention, there is provided a ocularimplant which releases an agent selected from the group consisting of ananthracycline, fluoropyrimidine, folic acid antagonist, podophylotoxin,camptothecin, hydroxyurea, or platinum complex. In one embodiment, theocular implant releases a fluoropyrimidine and in still anotherembodiment the fluoropyrimidine is 5-FU. In other embodiments, theocular implant further comprises a polymer wherein the agent is releasedfrom a polymer on the ocular implant. In certain embodiments, the ocularimplant has a polymer that is polyurethane or PLG. In relatedembodiments, the ocular implant is an intraocular lens or a contactlens. In still other embodiments, the ocular implant relaeases an agentthat is present on the ocular implant at a concentration which is lessthan the typical dosage and/or concentration that is used in thetreatment of cancer.

Within other aspects of the invention, compositions are providedcomprising a polymer and an anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex, wherein said anthracycline, fluoropyrimidine, folic acidantagonist, podophylotoxin, camptothecin, hydroxyurea, or platinumcomplex is present in said composition at a concentration of less thanany one of 10⁻⁴ M, 10⁻⁵ M, 10⁻⁶ M, or, 10⁻⁷ M.

Also provided methods for reducing or inhibiting infection associatedwith a medical implant, comprising the step of introducing a medicalimplant into a patient which has been coated with an anthracycline,fluoropyrimidine, folic acid antagonist, podophylotoxin, camptothecin,hydroxyurea, or platinum complex.

Within various embodiments of the above, the anthracycline isdoxorubicin or mitoxantrone, the fluoropyrimidine is 5-fluorouracil, thefolic acid antagonist is methotrexate, and the podophylotoxin isetoposide. Within further embodiments the composition further comprisesa polymer.

These and other aspects of the present invention will become evidentupon reference to the following detailed description and attacheddrawings. In addition, various references are set forth herein whichdescribe in more detail certain procedures or compositions (e.g.,compounds or agents and methods for making such compounds or agents,etc.), and are therefore incorporated by reference in their entirety.When PCT applications are referred to it is also understood that theunderlying or cited U.S. applications are also incorporated by referenceherein in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

Prior to setting forth the invention, it may be helpful to anunderstanding thereof to set forth definitions of certain terms thatwill be used hereinafter.

“Medical implant” refers to devices or objects that are implanted orinserted into a body. Representative examples include vascularcatheters, prosthetic heart valves, cardiac pacemakers, implantablecardioverter defibrillators, vascular grafts, ear, nose, or throatimplants, urological implants, endotracheal or tracheostomy tubes,dialysis catheters, CNS shunts, orthopedic implants, and ocularimplants.

As used herein, the term “about” or “consists essentially of” refers to±15% of any indicated structure, value, or range. Any numerical rangesrecited herein are to be understood to include any integer within therange and, where applicable (e.g., concentrations), fractions thereof,such as one tenth and one hundredth of an integer (unless otherwiseindicated).

Briefly, as noted above, the present invention discloses medicalimplants (as well as compositions and methods for making medicalimplants) which reduce the likelihood of infections in medical implants.More specifically, as noted above, infection is a common complication ofthe implantation of foreign bodies such as medical devices. Foreignmaterials provide an ideal site for micro-organisms to attach andcolonize. It is also hypothesized that there is an impairment of hostdefenses to infection in the microenvironment surrounding a foreignmaterial. These factors make medical implants particularly susceptibleto infection and make eradication of such an infection difficult, if notimpossible, in most cases.

Medical implant failure as a result of infection, with or without theneed to replace the implant, results in significant morbidity, mortalityand cost to the healthcare system. Since there is a wide array ofinfectious agents capable of causing medical implant infections, thereexists a significant unmet need for therapies capable of inhibiting thegrowth of a diverse spectrum of bacteria and fungi on implantabledevices. The present invention meets this need by providing drugs thatcan be released from an implantable device, and which have potentantimicrobial activity at extremely low doses. Further, these agentshave the added advantage that should resistance develop to thechemotherapeutic agent, the drug utilized in the coating would not beone which would be used to combat the subsequent infection (i.e., ifbacterial resistance developed it would be to an agent that is not usedas an antibiotic).

Discussed in more detail below are (I) Agents; (II) Compositions andFormulations; (III) Devices, and (IV) Clinical Applications.

I. Agents

Briefly, a wide variety of agents (also referred to herein as‘therapeutic agents’ or ‘drugs’) can be utilized within the context ofthe present invention, either with or without a carrier (e.g., apolymer; see section II below). Discussed in more detail below are (A)Anthracyclines (e.g., doxorubicin and mitoxantrone), (B)Fluoropyrimidines (e.g., 5-FU), (C) Folic acid antagonists (e.g.,methotrexate), (D) Podophylotoxins (e.g., etoposide), (E) Camptothecins,(F) Hydroxyureas, and (G) Platinum complexes (e.g., cisplatin).

A. Anthracyclines

Anthracyclines have the following general structure, where the R groupsmay be a variety of organic groups:

According to U.S. Pat. No. 5,594,158, suitable R groups are as follows:R₁ is CH₃ or CH₂OH; R₂ is daunosamine or H; R₃ and R₄ are independentlyone of OH, NO₂, NH₂, F, Cl, Br, I, CN, H or groups derived from these;R₅ is hydrogen, hydroxy, or methoxy; and R₆₋₈ are all hydrogen.Alternatively, R₅ and R₆ are hydrogen and R₇ and R₈ are alkyl orhalogen, or vice versa.

According to U.S. Pat. No. 5,843,903, R₁ may be a conjugated peptide.According to U.S. Pat. No. 4,296,105, R₅ may be an ether linked alkylgroup. According to U.S. Pat. No. 4,215,062, R₅ may be OH or an etherlinked alkyl group. R₁ may also be linked to the anthracycline ring by agroup other than C(O), such as an alkyl or branched alkyl group havingthe C(O) linking moiety at its end, such as —CH₂CH(CH₂—X)C(O)—R₁,wherein X is H or an alkyl group (see, e.g., U.S. Pat. No. 4,215,062).R₂ may alternately be a group linked by the functional group═N—NHC(O)—Y, where Y is a group such as a phenyl or substituted phenylring. Alternately R₃ may have the following structure:

in which R₉ is OH either in or out of the plane of the ring, or is asecond sugar moiety such as R₃. R₁₀ may be H or form a secondary aminewith a group such as an aromatic group, saturated or partially saturated5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S.Pat. No. 5,843,903). Alternately, R₁₀ may be derived from an amino acid,having the structure —C(O)CH(NHR₁₁)(R₁₂), in which R₁₁ is H, or forms aC₃₋₄ membered alkylene with R₁₂. R₁₂ may be H, alkyl, aminoalkyl, amino,hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Pat. No.4,296,105).

Exemplary anthracyclines are Doxorubicin, Daunorubicin, Idarubicin,Epirubicin, Pirarubicin, Zorubicin, and Carubicin. Suitable compoundshave the structures:

R₁ R₂ R₃ Doxorubicin: OCH₃ C(O)CH₂OH OH out of ring plane Epirubicin:(4′ epimer of OCH₃ C(O)CH₂OH OH in ring plane doxorubicin) Daunorubicin:OCH₃ C(O)CH₃ OH out of ring plane Idarubicin: H C(O)CH₃ OH out of ringplane Pirarubicin: OCH₃ C(O)CH₂OH

Zorubicin: OCH₃ C(CH₃)(═N)NHC(O)C₆H₅ OH Carubicin: OH C(O)CH₃ OH out ofring plane

Other suitable anthracyclines are Anthramycin, Mitoxantrone, Menogaril,Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin A₃, andPlicamycin having the structures:

Other representative anthracyclines include, FCE 23762 doxorubicinderivative (Quaglia et al., J. Liq. Chromatogr. 17(18):3911-3923, 1994),annamycin (Zou et al., J. Pharm. Sci. 82(11):1151-1154, 1993), ruboxyl(Rapoport et al., J. Controlled Release 58(2): 153-162, 1999),anthracycline disaccharide doxorubicin analogue (Pratesi et al., Clin.Cancer Res. 4(11):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and4′-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth.Commun. 28(6):1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al.,Proc. Nat'lAcad. Sci. U.S.A. 95(4):1794-1799, 1998), disaccharidedoxorubicin analogues (Arcamone et al., J. Nat'l Cancer Inst.89(16):1217-1223, 1997),4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)-α-L-lyxo-hexopyranosyl]adriamicinonedoxorubicin disaccharide analog (Monteagudo et al., Carbohydr. Res.300(1):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'lAcad. Sci. U.S.A. 94(2):652-656, 1997), morpholinyl doxorubicinanalogues (Duran et al., Cancer Chemother. Pharmacol. 38(3):210-216,1996), enaminomalonyl-β-alanine doxorubicin derivatives (Seitz et al.,Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin doxorubicinderivatives (Vrudhula et al., J. Med. Chem. 38(8):1380-5, 1995),hydroxyrubicin (Solary et al., Int. J. Cancer 58(1):85-94, 1994),methoxymorpholino doxorubicin derivative (Kuhl et al., Cancer Chemother.Pharmacol. 33(1):10-16, 1993), (6-maleimidocaproyl)hydrazone doxorubicinderivative (Willner et al., Bioconjugate Chem. 4(6):521-7, 1993),N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem.35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicinderivative (Ripamonti et al., Br. J. Cancer 65(5):703-7, 1992),N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al.,Biochim. Biophys. Acta 1118(1):83-90, 1991), polydeoxynucleotidedoxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta1129(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med.Chem. 34(8):2373-80. 1991), AD198 doxorubicin analogue (Traganos et al.,Cancer Res. 51(14):3682-9, 1991),4-demethoxy-3′-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des.Delivery 6(2):123-9, 1990), 4′-epidoxorubicin (Drzewoski et al., Pol. J.Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur. J. CancerClin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicinderivative (Scudder et at., J. Nat'l Cancer Inst. 80(16):1294-8, 1988),deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya etal., Vestn. Mosk. Univ., 16(Biol. 1):21-7, 1988), 4′-deoxydoxorubicin(Schoelzel et al., Leuk. Res. 10(12):1455-9, 1986),4-demethyoxy-4′-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr.Chemother. 16:285-70-285-77, 1983), 3′-deamino-3′-hydroxydoxorubicin(Horton et al., J. Antibiot 37(8):853-8, 1984), 4-demethyoxy doxorubicinanalogues (Barbieri et al., Drugs Exp. Clin. Res. 10(2):85-90, 1984),N-L-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc.Int. Symp. Tumor Pharmacother.), 179-81, 1983),3′-deamino-3′-(4-methoxy-1-piperidinyl)doxorubicin derivatives (U.S.Pat. No. 4,314,054), 3′-deamino-3′-(4-mortholinyl)doxorubicinderivatives (U.S. Pat. No. 4,301,277), 4′-deoxydoxorubicin and4′-o-methyldoxorubicin (Giuliani et al., Int J. Cancer 27(1):5-13,1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sci.67(12):1748-52, 1978), SM 5887 (Pharma Japan 1468:20, 1995), MX-2(Pharma Japan 1420:19, 1994), 4′-deoxy-13(S)-dihydro-4′-iododoxorubicin(EP 275966), morpholinyl doxorubicin derivatives (EPA 434960),3′-deamino-3′-(4-methoxy-1-piperidinyl)doxorubicin derivatives (U.S.Pat. No. 4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin(U.S. Pat. No. 5,004,606), 3′-deamino-3′-(3″-cyano-4″-morpholinyldoxorubicin;3′-deamino-3′-(3″-cyano-4″-morpholinyl)-13-dihydroxorubicin;(3′-deamino-3′-(3″-cyano-4″-morpholinyl)daunorubicin;3′-deamino-3′-(3″-cyano-4″-morpholinyl)-3-dihydrodaunorubicin; and3′-deamino-3′-(4″-morpholinyl-5-iminodoxorubicin and derivatives (U.S.Pat. No. 4,585,859), 3′-deamino-3′-(4-methoxy-1-piperidinyl)doxorubicinderivatives (U.S. Pat. No. 4,314,054) and3-deamino-3-(4-morpholinyl)doxorubicin derivatives (U.S. Pat. No.4,301,277).

B. Fluoropyrimidine Analogs

In another aspect, the therapeutic agent is a fluoropyrimidine analog,such as 5-fluorouracil, or an analog or derivative thereof, includingCarmofur, Doxifluridine, Emitefur, Tegafur, and Floxuridine. Exemplarycompounds have the structures:

R₁ R₂ 5-Fluorouracil H H Carmofur C(O)NH(CH₂)₅CH₃ H Doxifluridine A₁ HFloxuridine A₂ H Emitefur CH₂OCH₂CH₃ B Tegafur C H

Other suitable fluoropyrimidine analogs include 5-FudR(5-fluoro-deoxyuridine), or an analog or derivative thereof, including5-iododeoxyuridine (5-IudR), 5-bromodeoxyuridine (5-BudR), Fluorouridinetriphosphate (5-FUTP), and Fluorodeoxyuridine monophosphate (5-dFUMP).Exemplary compounds have the structures:

Other representative examples of fluoropyrimidine analogs includeN3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc.,Perkin Trans. 1(19):3145-3146, 1998), 5-fluorouracil derivatives with1,4-oxaheteroepane moieties (Gomez et al., Tetrahedron54(43):13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li,Anticancer Res. 17(1A):21-27, 1997), cis- andtrans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al., Br. J.Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil analogues(Hronowski & Szarek, Can. J. Chem. 70(4):1162-9, 1992),A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi20(11):513-15, 1989), N4-trimethoxybenzoyl-5′-deoxy-5-fluorocytidine and5′-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull.38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J.Pharmacobio-Dun. 3(9):478-81, 1980; Maehara et al., Chemotherapy (Base1)34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988),uracil-1-(2-tetrahydrofuryl)-5-fluorouracil (Anai et al., Oncology45(3):144-7, 1988),1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-fluorouracil (Suzuko etal., Mol. Pharmacol. 31(3):301-6, 1987), doxifluridine (Matuura et al.,Oyo Yakuri 29(5):803-31, 1985), 5′-deoxy-5-fluorouridine (Bollag &Hartmann, Eur. J. Cancer 16(4):427-32, 1980),1-acetyl-3-O-toluoyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci.28(1):49-66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP55059173), N′-(2-furanidyl)-5-fluorouracil (JP 53149985) and1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680).

These compounds are believed to function as therapeutic agents byserving as antimetabolites of pyrimidine.

C. Folic Acid Antagonists

In another aspect, the therapeutic agent is a folic acid antagonist,such as Methotrexate or derivatives or analogs thereof, includingEdatrexate, Trimetrexate, Raltitrexed, Piritrexim, Denopterin, Tomudex,and Pteropterin. Methotrexate analogs have the following generalstructure:

The identity of the R group may be selected from organic groups,particularly those groups set forth in U.S. Pat. Nos. 5,166,149 and5,382,582. For example, R₁ may be N, R₂ may be N or C(CH₃), R₃ and R₃′may H or alkyl, e.g., CH₃, R₄ may be a single bond or NR, where R is Hor alkyl group. R_(5,6,8) may be H, OCH₃, or alternately they can behalogens or hydro groups. R₇ is a side chain of the general structure:

wherein n=1 for methotrexate, n=3 for pteropterin. The carboxyl groupsin the side chain may be esterified or form a salt such as a Zn²⁺ salt.R₉ and R₁₀ can be NH₂ or may be alkyl substituted.

Exemplary folic acid antagonist compounds have the structures:

R₀ R₁ R₂ R₃ R₄ R₅ R₆ R₇ R₈ Methotrexate NH₂ N N H N(CH₃) H H A (n = 1) HEdatrexate NH₂ N N H CH(CH₂CH₃) H H A (n = 1) H Trimetrexate NH₂ CHC(CH₃) H NH H OCH₃ OCH₃ OCH₃ Pteropterin OH N N H NH H H A (n = 3) HDenopterin OH N N CH₃ N(CH₃) H H A (n = 1) H Peritrexim NH₂ N C(CH₃) Hsingle bond OCH₃ H H OCH₃

Other representative examples include 6-S-aminoacyloxymethylmercaptopurine derivatives (Harada et al., Chem. Pharm. Bull.43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol.Pharm. Bull. 18(11):1492-7, 1995),7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al.,Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J.Inorg. Biochem. 56(4):249-64, 1994), methyl-D-glucopyranosidemercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem.29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino etal., Khim.-Farm. Zh. 15(8):65-7, 1981); indoline ring and a modifiedornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka etal., Chem. Pharm. Bull. 45(7):1146-1150, 1997), alkyl-substitutedbenzene ring C bearing methotrexate derivatives (Matsuoka et al., Chem.Pharm. Bull. 44(12):2287-2293, 1996), benzoxazine or benzothiazinemoiety-bearing methotrexate derivatives (Matsuoka et al., J. Med. Chem.40(1):105-111, 1997), 10-deazaminopterin analogues (DeGraw et al., J.Med. Chem. 40(3):370-376, 1997), 5-deazaminopterin and5,10-dideazaminopterin methotrexate analogues (Piper et al., J. Med.Chem. 40(3):377-384, 1997), indoline moiety-bearing methotrexatederivatives (Matsuoka et al., Chem. Pharm. Bull. 44(7):1332-1337, 1996),lipophilic amide methotrexate derivatives (Pignatello et al., WorldMeet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995),L-threo-(2S,4S)-4-fluoroglutamic acid and DL-3,3-difluoroglutamicacid-containing methotrexate analogues (Hart et al., J. Med. Chem.39(1):56-65, 1996), methotrexate tetrahydroquinazoline analogue(Gangjee, et al., J. Heterocycl. Chem. 32(1):243-8, 1995),N-(α-aminoacyl)methotrexate derivatives (Cheung et al., Pteridines3(1-2):101-2, 1992), biotin methotrexate derivatives (Fan et al.,Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D-erythrou,threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al.,Biochem. Pharmacol. 42(12):2400-3, 1991), β,γ-methano methotrexateanalogues (Rosowsky et al., Pteridines 2(3):133-9, 1991),10-deazaminopterin (10-EDAM) analogue (Braakhuis et al., Chem. Biol.Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027-30,1989), γ-tetrazole methotrexate analogue (Kalman et al., Chem. Biol.Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7,1989), N-(L-α-aminoacyl)methotrexate derivatives (Cheung et al.,Heterocycles 28(2):751-8, 1989), meta and ortho isomers of aminopterin(Rosowsky et al., J. Med. Chem. 32(12):2582, 1989),hydroxymethylmethotrexate (DE 267495), γ-fluoromethotrexate (McGuire etal., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexatederivatives (Kumar et al., Cancer Res. 46(10):5020-3, 1986),gem-diphosphonate methotrexate analogues (WO 88/06158), α- andγ-substituted methotrexate analogues (Tsushima et al., Tetrahedron44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate analogues (U.S.Pat. No. 4,725,687), Nδ-acyl-Nα-(4-amino-4-deoxypteroyl)-L-ornithinederivatives (Rosowsky et al., J. Med. Chem. 31(7):1332-7, 1988), 8-deazamethotrexate analogues (Kuehl et al., Cancer Res. 48(6):1481-8, 1988),acivicin methotrexate analogue (Rosowsky et al., J. Med. Chem.30(8):1463-9, 1987), polymeric platinol methotrexate derivative(Carraher et al., Polym. Sci. Technol. (Plenum), 35(Adv. Biomed.Polym.):311-24, 1987), methotrexate-γ-dimyristoylphophatidylethanolamine(Kinsky et al., Biochim. Biophys. Acta 917(2):211-18, 1987),methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol.Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. PteridinesFolid Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986),poly-γ-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol.Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. PteridinesFolid Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986),deoxyuridylate methotrexate derivatives (Webber et al., Chem. Biol.Pteridines, Pteridines Folid Acid Deriv., Proc. Int. Symp. PteridinesFolid Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyllysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines,Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid AcidDeriv.: Chem., Biol. Clin. Aspects: 807-9, 1986),2,.omega.-diaminoalkanoid acid-containing methotrexate analogues(McGuire et al., Biochem. Pharmacol. 35(15):2607-13, 1986),polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol.122(Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues(Piper et al., J. Med. Chem. 29(6):1080-7, 1986), quinazolinemethotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1):155-8,1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl.Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid methotrexateanalogues (U.S. Pat. No. 4,490,529), γ-tert-butyl methotrexate esters(Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluorinatedmethotrexate analogues (Tsushima et al., Heterocycles 23(1):45-9, 1985),folate methotrexate analogue (Trombe, J. Bacteriol. 160(3):849-53,1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J.Med. Chem. —Chim. Ther. 19(3):267-73, 1984), poly (L-lysine)methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27(7):888-93,1984), dilysine and trilysine methotrexate derivates (Forsch & Rosowsky,J. Org. Chem. 49(7):1305-9, 1984), 7-hydroxymethotrexate (Fabre et al.,Cancer Res. 43(10):4648-52, 1983), poly-γ-glutamyl methotrexateanalogues (Piper & Montgomery, Adv. Exp. Med. Biol., 163(Folyl AntifolylPolyglutamates):95-100, 1983), 3′,5′-dichloromethotrexate (Rosowsky &Yu, J. Med. Chem. 26(10):1448-52, 1983), diazoketone andchloromethylketone methotrexate analogues (Gangjee et al., J. Pharm.Sci. 71(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexatehomologs (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectinderivatives of methotrexate (Lin et al., JNCI 66(3):523-8, 1981),polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol.17(1):105-10, 1980), halogentated methotrexate derivatives (Fox, JNCI58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al.,J. Med. Chem. 20(10):J1323-7, 1977), 7-methyl methotrexate derivativesand dichloromethotrexate (Rosowsky & Chen, J. Med. Chem.17(12):J1308-11, 1974), lipophilic methotrexate derivatives and3′,5′-dichloromethotrexate (Rosowsky, J. Med. Chem. 16(10):J1190-3,1973), deaza amethopterin analogues (Montgomery et al., Ann. N.Y. Acad.Sci. 186:J227-34, 1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteicacid and homocysteic acid methotrexate analogues (EPA 0142220);

These compounds are believed to act as antimetabolites of folic acid.

D. Podophyllotoxins

In another aspect, the therapeutic agent is a Podophyllotoxin, or aderivative or an analog thereof. Exemplary compounds of this type areEtoposide or Teniposide, which have the following structures:

Other representative examples of podophyllotoxins include Cu(II)-VP-16(etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7):1003-1008,1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al.,Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4β-amino etoposideanalogues (Hu, University of North Carolina Dissertation, 1992),γ-lactone ring-modified arylamino etoposide analogues (Zhou et al., J.Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi etal., Tetrahedron Lett. 34(45):7313-16, 1993), etoposide A-ring analogues(Kadow et al., Bioorg. Med. Chem. Lett. 2(1):17-22, 1992),4′-deshydroxy-4′-methyl etoposide (Saulnier et al., Bioorg. Med. Chem.Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues (Sinha etal., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy etoposideanalogues (Saulnier et al., J. Med. Chem. 32(7):1418-20, 1989).

These compounds are believed to act as Topoisomerase II Inhibitorsand/or DNA cleaving agents.

E. Camptothecins

In another aspect, the therapeutic agent is Camptothecin, or an analogor derivative thereof. Camptothecins have the following generalstructure.

In this structure, X is typically O, but can be other groups, e.g., NHin the case of 21-lactam derivatives. R₁ is typically H or OH, but maybe other groups, e.g., a terminally hydroxylated C₁₋₃ alkane. R₂ istypically H or an amino containing group such as (CH₃)₂NHCH₂, but may beother groups e.g., NO₂, NH₂, halogen (as disclosed in, e.g., U.S. Pat.No. 5,552,156) or a short alkane containing these groups. R₃ istypically H or a short alkyl such as C₂H₅. R₄ is typically H but may beother groups, e.g., a methylenedioxy group with R₁.

Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11),9-aminocamptothecin, 21-lactam-20(S)-camptothecin,10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin,10-hydroxycamptothecin. Exemplary compounds have the structures:

R₁ R₂ R₃ Camptothecin: H H H Topotecan: OH (CH₃)₂NHCH₂ H SN-38: OH HC₂H₅X: O for most analogs, NH for 21-lactam analogs

Camptothecins have the five rings shown here. The ring labeled E must beintact (the lactone rather than carboxylate form) for maximum activityand minimum toxicity.

Camptothecins are believed to function as Topoisomerase I Inhibitorsand/or DNA cleavage agents.

F. Hydroxyureas

The therapeutic agent of the present invention may be a hydroxyurea.Hydroxyureas have the following general structure:

Suitable hydroxyureas are disclosed in, for example, U.S. Pat. No.6,080,874, wherein R₁ is:

and R₂ is an alkyl group having 1-4 carbons and R₃ is one of H, acyl,methyl, ethyl, and mixtures thereof, such as a methylether.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.5,665,768, wherein R₁ is a cycloalkenyl group, for exampleN-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea; R₂is H or an alkyl group having 1 to 4 carbons and R₃ is H; X is H or acation.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.4,299,778, wherein R₁ is a phenyl group substituted with one or morefluorine atoms; R₂ is a cyclopropyl group; and R₃ and X is H.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Pat. No.5,066,658, wherein R₂ and R₃ together with the adjacent nitrogen form:

wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.

In one aspect, the hydroxyurea has the structure:

These compounds are thought to function by inhibiting DNA synthesis.

G. Platinum Complexes

In another aspect, the therapeutic agent is a platinum compound. Ingeneral, suitable platinum complexes may be of Pt(II) or Pt(IV) and havethis basic structure:

wherein X and Y are anionic leaving groups such as sulfate, phosphate,carboxylate, and halogen; R₁ and R₂ are alkyl, amine, amino alkyl anymay be further substituted, and are basically inert or bridging groups.For Pt(II) complexes Z₁ and Z₂ are non-existent. For Pt(IV) Z₁ and Z₂may be anionic groups such as halogen, hydroxy, carboxylate, ester,sulfate or phosphate. See, e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.

Suitable platinum complexes may contain multiple Pt atoms. See, e.g.,U.S. Pat. Nos. 5,409,915 and 5,380,897. For example bisplatinum andtriplatinum complexes of the type:

Exemplary platinum compounds are Cisplatin, Carboplatin, Oxaliplatin,and Miboplatin having the structures:

Other representative platinum compounds include (CPA)₂Pt[DOLYM] and(DACH)Pt[DOLYM] cisplatin (Choi et al., Arch. Pharmacal Res.22(2):151-156, 1999),Cis-[PtCl₂(4,7-H-5-methyl-7-oxo]1,2,4[triazolo[1,5-a]pyrimidine)₂](Navarro et al., J. Med. Chem. 41(3):332-338, 1998),[Pt(cis-1,4-DACH)(trans-Cl₂)(CBDCA)].½MeOH cisplatin (Shamsuddin et al.,Inorg. Chem. 36(25):5969-5971, 1997), 4-pyridoxate diammine hydroxyplatinum (Tokunaga et al., Pharm. Sci. 3(7):353-356, 1997), Pt(II) . . .Pt(II) (Pt₂[NHCHN(C(CH₂)(CH₃))]₄) (Navarro et al., Inorg. Chem.35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol.Res. 18(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatinanalogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298,1996), trans, cis-[Pt(OAc)₂I₂(en)] (Kratochwil et al., J. Med. Chem.39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine ligand(with sulfur-containing amino acids and glutathione) bearing cisplatinanalogues (Bednarski, J. Inorg. Biochem. 62(1):75, 1996),cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al., J.Inorg. Biochem. 61(4):291-301, 1996), 5′ orientational isomer ofcis-[Pt(NH₃)(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J. Am. Chem.Soc. 117(43):10702-12, 1995), chelating diamine-bearing cisplatinanalogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995),1,2-diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al.,J. Cancer Res. Clin. Oncol. 121(1):31-8, 1995),(ethylenediamine)platinum(II) complexes (Pasini et al., J. Chem. Soc.,Dalton Trans. 4:579-85, 1995), CI-973 cisplatin analogue (Yang et al.,Int. J. Oncol. 5(3):597-602, 1994), cis-diaminedichloroplatinum(II) andits analoguescis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(II)and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg.Biochem. 26(4):257-67, 1986; Fan et al., Cancer Res. 48(11):3135-9,1988; Heiger-Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawaet al., J. Exp. Clin. Cancer Res. 12(4):233-40, 1993; Murray et al.,Biochemistry 31(47):11812-17, 1992; Takahashi et al., Cancer Chemother.Pharmacol. 33(1):31-5, 1993),cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et al., Biochem.Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR2683529), (meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine)dichloroplatinum(II) (Bednarski et al., J. Med. Chem. 35(23):4479-85,1992), cisplatin analogues containing a tethered dansyl group (Hartwiget al., J. Am. Chem. Soc. 114(21):8292-3, 1992), platinum(II) polyamines(Siegmann et al., Inorg. Met. —Containing Polym. Mater., (Proc. Am.Chem. Soc. Int Symp.), 335-61, 1990),cis-(3H)dichloro(ethylenediamine)platinum(II) (Eastman, Anal. Biochem.197(2):311-15, 1991), trans-diamminedichloroplatinum(II) andcis-(Pt(NH₃)₂(N₃-cytosine)Cl) (Bellon & Lippard, Biophys. Chem.35(2-3):179-88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(II)and 3H-cis-1,2-diaminocyclohexane-malonatoplatinum (II) (Oswald et al.,Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989),diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1,2-diaminocyclohexane carrier ligand-bearing platinum analogues(Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988),aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al.,Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin,iproplatin and JM40 platinum analogues (Schroyen et al., Eur. J. CancerClin. Oncol. 24(8):1309-12, 1988), bidentate tertiary diamine-containingcisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2):125-34,1988), platinum(II), platinum(IV) (Liu & Wang, Shandong Yike DaxueXuebao 24(1):35-41, 1986),cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II) (carboplatin,JM8) and ethylenediammine-malonatoplatinum(II) (JM40) (Begg et al.,Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues(Harstrick et al., Int. J. Androl. 10(1); 139-45, 1987),(NPr4)2((PtCL4).cis-(PtCl2-(NH2Me)2)) (Brammer et al., J. Chem. Soc.,Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinumcomplexes (EPA 185225), and cis-dichloro(amino acid)(tert-butylamine)platinum(II) complexes (Pasini & Bersanetti, Inorg.Chim. Acta 107(4):259-67, 1985). These compounds are thought to functionby binding to DNA, i.e., acting as alkylating agents of DNA.

II. Compositions and Formulations

As noted above, therapeutic agents described herein may be formulated ina variety of manners, and thus may additionally comprise a carrier. Inthis regard, a wide variety of carriers may be selected of eitherpolymeric or non-polymeric origin. The polymers and non-polymer basedcarriers and formulations which are discussed in more detail below areprovided merely by way of example, not by way of limitation.

Within one embodiment of the invention a wide variety of polymers can beutilized to contain and/or deliver one or more of the agents discussedabove, including for example both biodegradable and non-biodegradablecompositions. Representative examples of biodegradable compositionsinclude albumin, collagen, gelatin, chitosan, hyaluronic acid, starch,cellulose and derivatives thereof (e.g., methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, cellulose acetate phthalate, cellulose acetatesuccinate, hydroxypropylmethylcellulose phthalate), alginates, casein,dextrans, polysaccharides, fibrinogen, poly(L-lactide), poly(D,Llactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(glycolide), poly(trimethylene carbonate), poly(hydroxyvalerate),poly(hydroxybutyrate), poly(caprolactone), poly(alkylcarbonate) andpoly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanone,poly(malic acid), poly(tartronic acid), polyanhydrides,polyphosphazenes, poly(amino acids), copolymers of such polymers andblends of such polymers (see generally, Illum, L., Davids, S. S. (eds.)“Polymers in Controlled Drug Delivery” Wright, Bristol, 1987; Arshady,J. Controlled Release 17:1-22, 1991; Pitt, Int. J. Phar. 59:173-196,1990; Holland et al., J. Controlled Release 4:155-0180, 1986).Representative examples of nondegradable polymers includepoly(ethylene-co-vinyl acetate) (“EVA”) copolymers, silicone rubber,acrylic polymers (e.g., polyacrylic acid, polymethylacrylic acid,poly(hydroxyethylmethacrylate), polymethylmethacrylate,polyalkylcyanoacrylate), polyethylene, polyproplene, polyamides (e.g.,nylon 6,6), polyurethane (e.g., poly(ester urethanes), poly(etherurethanes), poly(ester-urea), poly(carbonate urethanes)), polyethers(e.g., poly(ethylene oxide), poly(propylene oxide), Pluronics andpoly(tetramethylene glycol)) and vinyl polymers [e.g.,polyvinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetatephthalate)]. Polymers may also be developed which are either anionic(e.g., alginate, carrageenin, carboxymethyl cellulose and poly(acrylicacid), or cationic (e.g., chitosan, poly-L-lysine, polyethylenimine, andpoly (allyl amine)) (see generally, Dunn et al., J. Applied Polymer Sci.50:353-365, 1993; Cascone et al., J. Materials Sci.: Materials inMedicine 5:770-774, 1994; Shiraishi et al., Biol. Pharm. Bull.16(11):1164-1168, 1993; Thacharodi and Rao, Int'l J. Pharm. 120:115-118,1995; Miyazaki et al., Int'l J. Pharm. 118:257-263, 1995). Particularlypreferred polymeric carriers include poly(ethylene-co-vinyl acetate),polyurethane, acid, poly(caprolactone), poly(valerolactone),polyanhydrides, copolymers of poly(caprolactone) or poly(lactic acid)with a polyethylene glycol (e.g., MePEG), and blends thereof.

Other representative polymers include carboxylic polymers, polyacetates,polyacrylamides, polycarbonates, polyethers, polyesters, polyethylenes,polyvinylbutyrals, polysilanes, polyureas, polyurethanes, polyoxides,polystyrenes, polysulfides, polysulfones, polysulfonides,polyvinylhalides, pyrrolidones, rubbers, thermal-setting polymers,cross-linkable acrylic and methacrylic polymers, ethylene acrylic acidcopolymers, styrene acrylic copolymers, vinyl acetate polymers andcopolymers, vinyl acetal polymers and copolymers, epoxy, melamine, otheramino resins, phenolic polymers, and copolymers thereof, water-insolublecellulose ester polymers (including cellulose acetate propionate,cellulose acetate, cellulose acetate butyrate, cellulose nitrate,cellulose acetate phthalate, and mixtures thereof),polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide,polyvinyl alcohol, polyethers, polysaccharides, hydrophilicpolyurethane, polyhydroxyacrylate, dextran, xanthan, hydroxypropylcellulose, methyl cellulose, and homopolymers and copolymers ofN-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinylcaprolactam, other vinyl compounds having polar pendant groups, acrylateand methacrylate having hydrophilic esterifying groups, hydroxyacrylate,and acrylic acid, and combinations thereof; cellulose esters and ethers,ethyl cellulose, hydroxyethyl cellulose, cellulose nitrate, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,polyurethane, polyacrylate, natural and synthetic elastomers, rubber,acetal, nylon, polyester, styrene polybutadiene, acrylic resin,polyvinylidene chloride, polycarbonate, homopolymers and copolymers ofvinyl compounds, polyvinylchloride, polyvinylchloride acetate.

Representative examples of patents relating to polymers and theirpreparation include PCT Publication Nos. WO72827, 98/12243, 98/19713,98/41154, 99/07417, 00/33764, 00/21842, 00/09190, 00/09088, 00/09087,2001/17575 and 2001/15526 (as well as their corresponding U.S.applications), and U.S. Pat. Nos. 4,500,676, 4,582,865, 4,629,623,4,636,524, 4,713,448, 4,795,741, 4,913,743, 5,069,899, 5,099,013,5,128,326, 5,143,724, 5,153,174, 5,246,698, 5,266,563, 5,399,351,5,525,348, 5,800,412, 5,837,226, 5,942,555, 5,997,517, 6,007,833,6,071,447, 6,090,995, 6,099,563, 6,106,473, 6,110,483, 6,121,027,6,156,345, 6,179,817, 6,197,051, 6,214,901, 6,335,029, 6,344,035, which,as noted above, are all incorporated by reference in their entirety.

Polymers can be fashioned in a variety of forms, with desired releasecharacteristics and/or with specific desired properties. For example,polymers can be fashioned to release a therapeutic agent upon exposureto a specific triggering event such as pH (see, e.g., Heller et al.,“Chemically Self-Regulated Drug Delivery Systems,” in Polymers inMedicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp.175-188; Kang et al., J. Applied Polymer Sci. 48:343-354, 1993; Dong etal., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J.Controlled Release 15:141-152, 1991; Kim et al., J. Controlled Release28:143-152, 1994; Cornejo-Bravo et al., J. Controlled Release33:223-229, 1995; Wu and Lee, Pharm. Res. 10(10):1544-1547, 1993; Serreset al., Pharm. Res. 13(2):196-201, 1996; Peppas, “Fundamentals of pH-and Temperature-Sensitive Delivery Systems,” in Gurny et al. (eds.),Pulsatile Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH,Stuttgart, 1993, pp. 41-55; Doelker, “Cellulose Derivatives,” 1993, inPeppas and Langer (eds.), Biopolymers I, Springer-Verlag, Berlin).Representative examples of pH-sensitive polymers include poly(acrylicacid)-based polymers and derivatives (including, for example,homopolymers such as poly(aminocarboxylic acid), poly(acrylic acid),poly(methyl acrylic acid), copolymers of such homopolymers, andcopolymers of poly(acrylic acid) and acrylmonomers such as thosediscussed above). Other pH sensitive polymers include polysaccharidessuch as carboxymethyl cellulose, hydroxypropylmethylcellulose phthalate,hydroxypropyl-methylcellulose acetate succinate, cellulose acetatetrimellilate, chitosan and alginates. Yet other pH sensitive polymersinclude any mixture of a pH sensitive polymer and a water solublepolymer.

Likewise, polymers can be fashioned which are temperature sensitive(see, e.g., Chen et al., “Novel Hydrogels of a Temperature-SensitivePluronic Grafted to a Bioadhesive Polyacrylic Acid Backbone for VaginalDrug Delivery,” in Proceed. Intern. Symp. Control. Rel. Bioact Mater.22:167-168, Controlled Release Society, Inc., 1995; Okano, “MolecularDesign of Stimuli-Responsive Hydrogels for Temporal Controlled DrugDelivery,” in Proceed. Intern. Symp. Control. Rel. Bioact. Mater.22:111-112, Controlled Release Society, Inc., 1995; Johnston et al.,Pharm. Res. 9(3):425-433, 1992; Tung, Int'l J. Pharm. 107:85-90, 1994;Harsh and Gehrke, J. Controlled Release 17:175-186, 1991; Bae et al.,Pharm. Res. 8(4):531-537, 1991; Dinarvand and D'Emanuele, J. ControlledRelease 36:221-227, 1995; Yu and Grainger, “Novel Thermo-sensitiveAmphiphilic Gels: Poly N-isopropylacrylamide-co-sodiumacrylate-co-n-N-alkylacrylamide Network Synthesis and PhysicochemicalCharacterization,” Dept. of Chemical & Biological Sci., Oregon GraduateInstitute of Science & Technology, Beaverton, Oreg., pp. 820-821; Zhouand Smid, “Physical Hydrogels of Associative Star Polymers,” PolymerResearch Institute, Dept. of Chemistry, College of Environmental Scienceand Forestry, State Univ. of New York, Syracuse, N.Y., pp. 822-823;Hoffman et al., “Characterizing Pore Sizes and Water ‘Structure’ inStimuli-Responsive Hydrogels,” Center for Bioengineering, Univ. ofWashington, Seattle, Wash., p. 828; Yu and Grainger, “Thermo-sensitiveSwelling Behavior in Crosslinked N-isopropylacrylamide Networks:Cationic, Anionic and Ampholytic Hydrogels,” Dept. of Chemical &Biological Sci., Oregon Graduate Institute of Science & Technology,Beaverton, Oreg., pp. 829-830; Kim et al., Pharm. Res. 9(3):283-290,1992; Bae et al., Pharm. Res. 8(5):624-628, 1991; Kono et al., J.Controlled Release 30:69-75, 1994; Yoshida et al., J. Controlled Release32:97-102, 1994; Okano et al., J. Controlled Release 36:125-133, 1995;Chun and Kim, J. Controlled Release 38:39-47, 1996; D'Emanuele andDinarvand, Intl J. Pharm. 118:237-242, 1995; Katono et al., J.Controlled Release 16:215-228, 1991; Hoffman, “Thermally ReversibleHydrogels Containing Biologically Active Species,” in Migliaresi et al.(eds.), Polymers in Medicine III, Elsevier Science Publishers B.V.,Amsterdam, 1988, pp. 161-167; Hoffman, “Applications of ThermallyReversible Polymers and Hydrogels in Therapeutics and Diagnostics,” inThird International Symposium on Recent Advances in Drug DeliverySystems, Salt Lake City, Utah, Feb. 24-27, 1987, pp. 297-305; Gutowskaet al., J. Controlled Release 22:95-104, 1992; Palasis and Gehrke, J.Controlled Release 18:1-12, 1992; Paavola et al., Pharm. Res.12(12):1997-2002, 1995).

Representative examples of thermogelling polymers include homopolymerssuch as poly(N-methyl-N-n-propylacrylamide), poly(N-n-propylacrylamide),poly(N-methyl-N-isopropylacrylamide), poly(N-n-propylmethacrylamide),poly(N-isopropylacrylamide), poly(N, n-diethylacrylamide),poly(N-isopropylmethacrylamide), poly(N-cyclopropylacrylamide),poly(N-ethylmethyacrylamide), poly(N-methyl-N-ethylacrylamide),poly(N-cyclopropylmethacrylamide) and poly(N-ethylacrylamide). Moreoverthermogelling polymers may be made by preparing copolymers between(among) monomers of the above, or by combining such homopolymers withother water soluble polymers such as acrylmonomers (e.g., acrylic acidand derivatives thereof such as methylacrylic acid, acrylate andderivatives thereof such as butyl methacrylate, acrylamide, andN-n-butyl acrylamide).

Other representative examples of thermogelling cellulose etherderivatives such as hydroxypropyl cellulose, methyl cellulose,hydroxypropylmethyl cellulose, ethylhydroxyethyl cellulose, andPluronics, such as F-127.

A wide variety of forms may be fashioned by the polymers of the presentinvention, including for example, rod-shaped devices, pellets, slabs,particulates, micelles, films, molds, sutures, threads, gels, creams,ointments, sprays or capsules (see, e.g., Goodell et al., Am. J. Hosp.Pharm. 43:1454-1461, 1986; Langer et al., “Controlled release ofmacromolecules from polymers”, in Biomedical Polymers, PolymericMaterials and Pharmaceuticals for Biomedical Use, Goldberg, E. P.,Nakagim, A. (eds.) Academic Press, pp. 113-137, 1980; Rhine et al., J.Pharm. Sci. 69:265-270, 1980; Brown et al., J. Pharm. Sci. 72:1181-1185,1983; and Bawa et al., J. Controlled Release 1:259-267, 1985). Agentsmay be incorporated by dissolution in the polymer, occlusion in thematrices of the polymer, bound by covalent linkages, or encapsulated inmicrocapsules. Within certain preferred embodiments of the invention,therapeutic compositions are provided in non-capsular formulations, suchas coatings microspheres (ranging from nanometers to micrometers insize), pastes, threads or sutures of various size, films and sprays.

Other compounds which can be utilized to carry and/or deliver the agentsprovided herein include vitamin-based compositions (e.g., based onvitamins A, D, E and/or K, see, e.g., PCT publication Nos. WO 98/30205and WO 00/71163) and liposomes (see, U.S. Pat. Nos. 5,534,499,5,683,715, 5,776,485, 5,882,679, 6,143,321, 6,146,659, 6,200,598, andPCT Publication Nos. WO 98/34597, WO 99/65466, WO 00/01366, WO 00/53231,WO 99/35162, WO 00/117508, WO 00/125223, WO 00/149,268, WO 00/1565438,and WO 00/158455).

Preferably, therapeutic compositions of the present invention arefashioned in a manner appropriate to the intended use. Within certainaspects of the present invention, the therapeutic composition should bebiocompatible, and release one or more agents over a period of severaldays to months. Further, therapeutic compositions of the presentinvention should preferably be stable for several months and capable ofbeing produced, and maintained under sterile conditions.

Within certain aspects of the present invention, therapeuticcompositions may be fashioned in any size ranging from 50 nm to 500 μm,depending upon the particular use. Alternatively, such compositions mayalso be readily applied as a “spray” which solidifies into a film orcoating. Such sprays may be prepared from microspheres of a wide arrayof sizes, including for example, from 0.1 μm to 9 μm, from 10 μm to 30μm and from 30 μm to 100 μm.

Therapeutic compositions of the present invention may also be preparedin a variety of “paste” or gel forms. For example, within one embodimentof the invention, therapeutic compositions are provided which are liquidat one temperature (e.g., temperature greater than 37° C.) and solid orsemi-solid at another temperature (e.g., ambient body temperature, orany temperature lower than 37° C.). Also included are polymers, such asPluronic F-127, which are liquid at a low temperature (e.g., 4° C.) anda gel at body temperature. Such “thermopastes” may be readily made giventhe disclosure provided herein.

Within yet other aspects of the invention, the therapeutic compositionsof the present invention may be formed as a film. Preferably, such filmsare generally less than 5, 4, 3, 2 or 1 mm thick, more preferably lessthan 0.75 mm or 0.5 mm thick, and most preferably less than 500 μm. Suchfilms are preferably flexible with a good tensile strength (e.g.,greater than 50, preferably greater than 100, and more preferablygreater than 150 or 200 N/cm²), good adhesive properties (i.e., readilyadheres to moist or wet surfaces), and have controlled permeability.

Within certain embodiments of the invention, the therapeuticcompositions can also comprise additional ingredients such assurfactants (e.g., Pluronics such as F-127, L-122, L-92, L-81, andL-61).

Within further aspects of the present invention, polymers are providedwhich are adapted to contain and release a hydrophobic compound, thecarrier containing the hydrophobic compound in combination with acarbohydrate, protein or polypeptide. Within certain embodiments, thepolymeric carrier contains or comprises regions, pockets or granules ofone or more hydrophobic compounds. For example, within one embodiment ofthe invention, hydrophobic compounds may be incorporated within a matrixwhich contains the hydrophobic compound, followed by incorporation ofthe matrix within the polymeric carrier. A variety of matrices can beutilized in this regard, including for example, carbohydrates andpolysaccharides, such as starch, cellulose, dextran, methylcellulose,and hyaluronic acid, proteins or polypeptides such as albumin, collagenand gelatin. Within alternative embodiments, hydrophobic compounds maybe contained within a hydrophobic core, and this core contained within ahydrophilic shell.

Other carriers that may likewise be utilized to contain and deliver theagents described herein include: hydroxypropyl β-cyclodextrin (Cserhatiand Hollo, Int J. Pharm. 108:69-75, 1994), liposomes (see, e.g., Sharmaet al., Cancer Res. 53:5877-5881, 1993; Sharma and Straubinger, Pharm.Res. 11(60):889-896, 1994; WO 93/18751; U.S. Pat. No. 5,242,073),liposome/gel (WO 94/26254), nanocapsules (Bartoli et al., J.Microencapsulation 7(2):191-197, 1990), micelles (Alkan-Onyuksel et al.,Pharm. Res. 11(2):206-212, 1994), implants (Jampel et al., Invest.Ophthalm. Vis. Science 34(11): 3076-3083, 1993; Walter et al., CancerRes. 54:22017-2212, 1994), nanoparticles (Violante and Lanzafame PMCR),nanoparticles—modified (U.S. Pat. No. 5,145,684), nanoparticles (surfacemodified) (U.S. Pat. No. 5,399,363), taxol emulsion/solution (U.S. Pat.No. 5,407,683), micelle (surfactant) (U.S. Pat. No. 5,403,858),synthetic phospholipid compounds (U.S. Pat. No. 4,534,899), gas bornedispersion (U.S. Pat. No. 5,301,664), foam, spray, gel, lotion, cream,ointment, dispersed vesicles, particles or droplets solid- orliquid-aerosols, microemulsions (U.S. Pat. No. 5,330,756), polymericshell (nano- and micro-capsule) (U.S. Pat. No. 5,439,686), taxoid-basedcompositions in a surface-active agent (U.S. Pat. No. 5,438,072), liquidemulsions (Tarr et al., Pharm Res. 4:62-165, 1987), nanospheres (Haganet al., Proc. Intern. Symp. Control Rel. Bioact. Mater. 22, 1995; Kwonet al., Pharm Res. 12(2):192-195; Kwon et al., Pharm Res. 10(7):970-974;Yokoyama et al., J. Contr. Rel. 32:269-277, 1994; Gref et al., Science263:1600-1603, 1994; Bazile et al., J. Pharm. Sci. 84:493-498, 1994) andimplants (U.S. Pat. No. 4,882,168).

The agents provided herein can also be formulated as a sterilecomposition (e.g., by treating the composition with ethylene oxide or byirradiation), packaged with preservatives or other suitable excipientssuitable for administration to humans. Similarly, the devices providedherein (e.g., coated catheter) may be sterilized and prepared suitablefor implantation into humans.

III. Medical Implants

A. Representative Medical Implants

A wide variety of implants or devices can be coated with or otherwiseconstructed to contain and/or release the therapeutic agents providedherein. Representative examples include cardiovascular devices (e.g.,implantable venous catheters, venous ports, tunneled venous catheters,chronic infusion lines or ports, including hepatic artery infusioncatheters, pacemakers and pacesmaker leads (see, e.g., U.S. Pat. Nos.4,662,382, 4,782,836, 4,856,521, 4,860,751, 5,101,824, 5,261,419,5,284,491, 6,055,454, 6,370,434, and 6,370,434), implantabledefibrillators (see, e.g., U.S. Pat. Nos. 3,614,954, 3,614,955,4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953, 5,776,165,6,067,471, 6,169,923, and 6,152,955)); neurologic/neurosurgical devices(e.g., ventricular peritoneal shunts, ventricular atrial shunts, nervestimulator devices, dural patches and implants to prevent epiduralfibrosis post-laminectomy, devices for continuous subarachnoidinfusions); gastrointestinal devices (e.g., chronic indwellingcatheters, feeding tubes, portosystemic shunts, shunts for ascites,peritoneal implants for drug delivery, peritoneal dialysis catheters,and suspensions or solid implants to prevent surgical adhesions);genitourinary devices (e.g., uterine implants, including intrauterinedevices (IUDs) and devices to prevent endometrial hyperplasia, fallopiantubal implants, including reversible sterilization devices, fallopiantubal stents, artificial sphincters and periurethral implants forincontinence, ureteric stents, chronic indwelling catheters, bladderaugmentations, or wraps or splints for vasovasostomy, central venouscatheters (see, e.g., U.S. Pat. Nos. 3,995,623, 4,072,146 4,096,860,4,099,528, 4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329,4,960,409, 5,176,661, 5,916,208), urinary catheters (see, e.g. U.S. Pat.Nos. 2,819,718, 4,227,533, 4,284,459, 4,335,723, 4,701,162, 4,571,241,4,710,169, and 5,300,022,)); prosthetic heart valves (see, e.g., U.S.Pat. Nos. 3,656,185, 4,106,129, 4,892,540, 5,528,023, 5,772,694,6,096,075, 6,176,877, 6,358,278, and 6,371,983), vascular grafts (see,e.g. 3,096,560, 3,805,301, 3,945,052, 4,140,126, 4,323,525, 4,355,426,4,475,972, 4,530,113, 4,550,447, 4,562,596, 4,601,718, 4,647,416,4,878,908, 5,024,671, 5,104,399, 5,116,360, 5,151,105, 5,197,977,5,282,824, 5,405,379, 5,609,624, 5,693,088, and 5,910,168),opthalmologic implants (e.g., multino implants and other implants forneovascular glaucoma, drug eluting contact lenses for pterygiums,splints for failed dacrocystalrhinostomy, drug eluting contact lensesfor corneal neovascularity, implants for diabetic retinopathy, drugeluting contact lenses for high risk corneal transplants);otolaryngology devices (e.g., ossicular implants, Eustachian tubesplints or stents for glue ear or chronic otitis as an alternative totranstempanic drains); plastic surgery implants (e.g., breast implantsor chin implants), catheter cuffs and orthopedic implants (e.g.,cemented orthopedic prostheses).

B. Methods of Making Medical Implants Having Therapeutic Agents

Implants and other surgical or medical devices may be covered, coated,contacted, combined, loaded, filled, associated with, or otherwiseadapted to release therapeutic agents compositions of the presentinvention in a variety of manners, including for example: (a) bydirectly affixing to the implant or device a therapeutic agent orcomposition (e.g., by either spraying the implant or device with apolymer/drug film, or by dipping the implant or device into apolymer/drug solution, or by other covalent or noncovalent means); (b)by coating the implant or device with a substance, such as a hydrogel,which will in turn absorb the therapeutic composition (or therapeuticfactor above); (c) by interweaving therapeutic composition coated thread(or the polymer itself formed into a thread) into the implant or device;(d) by inserting the implant or device into a sleeve or mesh which iscomprised of or coated with a therapeutic composition; (e) constructingthe implant or device itself with a therapeutic agent or composition; or(f) by otherwise adapting the implant or device to release thetherapeutic agent. Within preferred embodiments of the invention, thecomposition should firmly adhere to the implant or device during storageand at the time of insertion. The therapeutic agent or compositionshould also preferably not degrade during storage, prior to insertion,or when warmed to body temperature after insertion inside the body (ifthis is required). In addition, it should preferably coat or cover thedesired areas of the implant or device smoothly and evenly, with auniform distribution of therapeutic agent. Within preferred embodimentsof the invention, the therapeutic agent or composition should provide auniform, predictable, prolonged release of the therapeutic factor intothe tissue surrounding the implant or device once it has been deployed.For vascular stents, in addition to the above properties, thecomposition should not render the stent thrombogenic (causing bloodclots to form), or cause significant turbulence in blood flow (more thanthe stent itself would be expected to cause if it was uncoated).

Within certain embodiments of the invention, a therapeutic agent can bedeposited directly onto all or a portion of the device (see, e.g., U.S.Pat. Nos. 6,096,070 and 6,299,604), or admixed with a delivery system orcarrier (e.g., a polymer, liposome, or vitamin as discussed above) whichis applied to all or a portion of the device (see the patents, patentapplications, and references listed above under “Compositions andFormulations.”

Within certain aspects of the invention, therapeutic agents can beattached to a medical implant using non-covalent attachments. Forexample, for compounds that are relatively sparingly water soluble orwater insoluble, the compound can be dissolved in an organic solvent aspecified concentration. The solvent chosen for this application wouldnot result in dissolution or swelling of the polymeric device surface.The medical implant can then be dipped into the solution, withdrawn andthen dried (air dry and/or vacuum dry). Alternatively, this drugsolution can be sprayed onto the surface of the implant. This can beaccomplished using current spray coating technology. The releaseduration for this method of coating would be relatively short and wouldbe a function of the solubility of the drug in the body fluid in whichit was placed.

In another aspect, a therapeutic agent can be dissolved in a solventthat has the ability to swell or partially dissolve the surface of apolymeric implant. Depending on the solvent/implant polymer combination,the implant could be dipped into the drug solution for a period of timesuch that the drug can diffuse into the surface layer of the polymericdevice. Alternatively the drug solution can be sprayed onto all or apart of the surface of the implant. The release profile of the drugdepends upon the solubility of the drug in the surface polymeric layer.Using this approach, one would ensure that the solvent does not resultin a significant distortion or dimensional change of the medicalimplant.

If the implant is composed of materials that do not allow incorporationof a therapeutic agent into the surface layer using the above solventmethod, one can treat the surface of the device with a plasmapolymerization method such that a thin polymeric layer is deposited ontothe device surface. Examples of such methods include parylene coating ofdevices, and the use of various monomers such hydrocyclosiloxanemonomers, acrylic acid, acrylate monomers, methacrylic acid ormethacrylate monomers. One can then use the dip coating or spray coatingmethods described above to incorporate the therapeutic agent into thecoated surface of the implant.

For therapeutic agents that have some degree of water solubility, theretention of these compounds on a device are relatively short-term. Fortherapeutic agents that contain ionic groups, it is possible toionically complex these agents to oppositely charged compounds that havea hydrophobic component. For example therapeutic agents containing aminegroups can be complexed with compounds such as sodium dodecyl sulfate(SDS). Compounds containing carboxylic groups can be complexed withtridodecymethyammonium chloride (TDMAC). Mitoxantrone, for example, hastwo secondary amine groups and comes as a chloride salt. This compoundcan be added to sodium dodecyl sulfate in order to form a complex. Thiscomplex can be dissolved in an organic solvent which can then be dipcoated or spray coated. Doxorubicin has an amine group and could thusalso be complexed with SDS. This complex could then be applied to thedevice by dip coating or spray coating methods. Methotrexate, forexample contains 2 carboxylic acid groups and could thus be complexedwith TDMAC and then coated onto the medical implant.

For therapeutic agents that have the ability to form ionic complexes orhydrogen bonds, the release of these agents from the device can bemodified by the use of organic compounds that have the ability to formionic or hydrogen bonds with the therapeutic agent. As described above,a complex between the ionically charged therapeutic agent and anoppositely charged hydrophobic compound can be prepared prior toapplication of this complex to the medical implant. In anotherembodiment, a compound that has the ability to form ionic or hydrogenbond interactions with the therapeutic agent can be incorporated intothe implant during the manufacture process, or during the coatingprocess. Alternatively, this compound can be incorporated into a coatingpolymer that is applied to the implant or during the process of loadingthe therapeutic agent into or onto the implant. These agents can includefatty acids (e.g., palmitic acid, stearic acid, lauric acid), aliphaticacids, aromatic acids (e.g., benzoic acid, salicylic acid),cylcoaliphatic acids, aliphatic (stearyl alcohol, lauryl alcohol, cetylalcohol) and aromatic alcohols alco multifunctional alcohols (e.g.,citric acid, tartaric acid, pentaerithratol), lipids (e.g., phosphatidylcholine, phosphatidylethanolamine), carbohydrates, sugars, spermine,spermidine, aliphatic and aromatic amines, natural and synthetic aminoacids, peptides or proteins. For example, a fatty acid such as palmiticacid can be used to modulate the release of 5-Fluoruracil from theimplant.

For therapeutic agents that have the ability to form ionic complexes orhydrogen bonds, the release of these agents from the implant can bemodified by the use of polymers that have the ability to form ionic orhydrogen bonds with the therapeutic agent. For example, therapeuticagents containing amine groups can form ionic complexes with sulfonic orcarboxylic pendant groups or end-groups of a polymer. Examples ofpolymers that can be used for this application include, but are notlimited to polymers and copolymers that are prepared using acrylic acid,methacrylic acid, sodium styrene sulfonate, styrene sulfonic acid,maleic acid or 2-acrylamido-2-methyl propane sulfonic acid. Polymersthat have been modified by sulfonation post-polymerization can also beused in this application. The medical implant, for example, can becoated with, or prepared with, a polymer that comprises nafion, asulfonated fluoropolymer. This medical device can then be dipped into asolution that comprises the amine-containing therapeutic agent. Theamine-containing therapeutic agent can also be applied by a spraycoating process. Methotrexate and doxorubicin are examples oftherapeutic agents that can be used in this application.

It is known that the presence of bacteria on the implant surface canresult in a localized decrease in pH. For polymers that comprise ionicexchange groups, for example, carboxylic groups, these polymers can havea localized increase in release of the therapeutic agent in response tothe localized decrease in pH as a result of the presence of thebacteria. For therapeutic agents that contain carboxylic acid groups,polymers with pendant end-groups comprising primary, secondary, tertiaryor quaternary amines can be used to modulate the release of thetherapeutic agent.

Therapeutic agents with available functional groups can be covalentlyattached to the medical implant surface using several chemical methods.If the polymeric material used to manufacture the implant has availablesurface functional groups then these can be used for covalent attachmentof the agent. For example, if the implant surface contains carboxylicacid groups, these groups can be converted to activated carboxylic acidgroups (e.g acid chlorides, succinimidyl derivatives, 4-nitrophenylester derivatives etc). These activated carboxylic acid groups can thenbe reacted with amine functional groups that are present on thetherapeutic agent (e.g., methotrexate, mitoxantrone).

For surfaces that do not contain appropriate functional groups, thesegroups can be introduced to the polymer surface via a plasma treatmentregime. For example, carboxylic acid groups can be introduced via aplasma treatment process (e.g., the use of O₂ and/or CO₂ as a componentin the feed gas mixture). The carboxylic acid groups can also beintroduced using acrylic acid or methacrylic acid in the gas stream.These carboxylic acid groups can then be converted to activatedcarboxylic acid groups (e.g., acid chlorides, succinimidyl derivatives,4-nitrophenyl ester derivatives, etc.) that can subsequently be reactedwith amine functional groups that are present on the therapeutic agent.

In addition to direct covalent bonding to the implant surface, thetherapeutic agents with available functional groups can be covalentlyattached to the medical implant via a linker. These linkers can bedegradable or non-degradable. Linkers that are hydrolytically orenzymatically cleaved are preferred. These linkers can comprise azo,ester, amide, thioester, anhydride, or phosphoester bonds.

To further modulate the release of the therapeutic agent from themedical implant, portions of or the entire medical implant may befurther coated with a polymer. The polymer coating can comprise thepolymers described above. The polymer coating can be applied by a dipcoating process, a spray coating process or a plasma deposition process.This coating can, if desired, be further crosslinked using thermal,chemical, or radiation (e.g., visible light, ultraviolet light, e-beam,gamma radiation, x-ray radiation) techniques in order to furthermodulate the release of the therapeutic agent from the medical implant.

This polymer coating can further contain agents that can increase theflexibility (e.g., plasticizer—glycerol, triethyl citrate), lubricity(e.g., hyaluronic acid), biocompatibility or hemocompatability (e.g.,heparin) of the coating.

The methods above describe methods for incorporation of a therapeuticagent into or onto a medical implant. Additional antibacterial orantifungal agents can also be incorporated into or onto the medicalimplant. These antibacterial or antifungal agents can be incorporatedinto or onto the medical implant prior to, simultaneously or after theincorporation of the therapeutic agents, described above, into or ontothe medical implant. Agents that can be used include, but are notlimited to silver compounds (e.g., silver chloride, silver nitrate,silver oxide), silver ions, silver particles, iodine, povidone/iodine,chlorhexidine, 2-p-sulfanilyanilinoethanol, 4,4′-sulfinyldianiline,4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin,amoxicillin, amphotericin B, ampicillin, apalcillin, apicycline,apramycin, arbekacin, aspoxicillin, azidamfenicol, azithromycin,aztreonam, bacitracin, bambermycin(s), biapenem, brodimoprim, butirosin,capreomycin, carbenicillin, carbomycin, carumonam, cefadroxil,cefamandole, cefatrizine, cefbuperazone, cefclidin, cefdinir,cefditoren, cefepime, cefetamet, cefixime, cefinenoxime, cefminox,cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan,cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome, cefprozil,cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam,cephalexin, cephaloglycin, cephalosporin C, cephradine, chloramphenicol,chlortetracycline, ciprofloxacin, clarithromycin, clinafloxacin,clindamycin, clomocycline, colistin, cyclacillin, dapsone,demeclocycline, diathymosulfone, dibekacin, dihydrostreptomycin,dirithromycin, doxycycline, enoxacin, enviomycin, epicillin,erythromycin, flomoxef, fortimicin(s), gentamicin(s), glucosulfonesolasulfone, gramicidin S, gramicidin(s), grepafloxacin, guamecycline,hetacillin, imipenem, isepamicin, josamycin, kanamycin(s),leucomycin(s), lincomycin, lomefloxacin, lucensomycin, lymecycline,meclocycline, meropenem, methacycline, micronomicin, midecamycin(s),minocycline, moxalactam, mupirocin, nadifloxacin, natamycin, neomycin,netilmicin, norfloxacin, oleandomycin, oxytetracycline,p-sulfanilylbenzylamine, panipenem, paromomycin, pazufloxacin,penicillin N, pipacycline, pipemidic acid, polymyxin, primycin,quinacillin, ribostamycin, rifamide, rifampin, rifamycin SV,rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin,rolitetracycline, rosaramycin, roxithromycin, salazosulfadimidine,sancycline, sisomicin, sparfloxacin, spectinomycin, spiramycin,streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin,temafloxacin, temocillin, tetracycline, tetroxoprim, thiamphenicol,thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin,tosufloxacin, trimethoprim, trospectomycin, trovafloxacin,tuberactinomycin, vancomycin, azaserine, candicidin(s), chlorphenesin,dermostatin(s), filipin, fungichromin, mepartricin, nystatin,oligomycin(s), ciproflaxacin, norfloxacin, ofloxacin, pefloxacin,enoxacin, rosoxacin, amifloxacin, fleroxacin, temafloaxcin,lomefloxacin, perimycin A or tubercidin, and the like.

IV. Clinical Applications

In order to further the understanding of the invention, discussed inmore detail below are various clinical applications for thecompositions, methods and devices provided herein.

Briefly, as noted above, within one aspect of the invention methods areprovided for preventing, reducing, and/or inhibiting an infectionassociated with a medical device or implant, comprising the step ofintroducing into a patient a medical implant which releases achemotherapeutic agent, wherein the chemotherapeutic agent reduces,inhibits, or prevents the growth or transmission of foreign organisms(e.g., bacteria, fungi, or viruses). As used herein, agents that reduce,inhibit, or prevent the growth or transmission of foreign organisms in apatient means that the growth or transmission of a foreign organism isreduced, inhibited, or prevented in a statistically significant mannerin at least one clinical outcome, or by any measure routinely used bypersons of ordinary skill in the art as a diagnostic criterion indetermining the same. In a preferred embodiment, the medical implant hasbeen covered or coated with an anthracycline (e.g., doxorubicin andmitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist(e.g., methotrexate), podophylotoxin (e.g., etoposide), camptothecin,hydroxyurea, and/or a platinum complexe (e.g., cisplatin).

Particularly preferred agents which are utilized within the context ofthe present invention should have an MIC of less than or equal to anyone of 10⁻⁴M, 10⁻⁵M, 10⁻⁶M, or, 10⁻⁷M. Furthermore, particularlypreferred agents are suitable for use at concentrations less than that10%, 5%, or even 1% of the concentration typically used inchemotherapeutic applications (Goodman and Gilman's The PharmacologicalBasis of Therapeutics. Editors J. G. Hardman, L. L. Limbird. Consultingeditor A. Goodman Gilman Tenth Edition. McGraw-Hill Medical publishingdivision. 10th edition, 2001, 2148 pp.). Finally, the devices shouldpreferably be provided sterile, and suitable for use in humans.

A. Vascular Catheter-Associated Infections

More than 30 million patients receive infusion therapy annually in theUnited States. In fact, 30% of all hospitalized patients have at leastone vascular catheter in place during their stay in hospital. A varietyof medical devices are used for infusion therapy including, but notrestricted to, peripheral intravenous catheters, central venouscatheters, total parenteral nutrition catheters, peripherally insertedcentral venous catheters (PIC lines), totally implanted intravascularaccess devices, flow-directed balloon-tipped pulmonary artery catheters,arterial lines, and long-term central venous access catheters (Hickmanlines, Broviac catheters).

Unfortunately, vascular access catheters are prone to infection by avariety of bacteria and are a common cause of bloodstream infection. Ofthe 100,000 bloodstream infections in US hospitals each year, many arerelated to the presence of an intravascular device. For example, 55,000cases of bloodstream infections are caused by central venous catheters,while a significant percentage of the remaining cases are related toperipheral intravenous catheters and arterial lines.

Bacteremia related to the presence of intravascular devices is not atrivial clinical concern: 50% of all patients developing this type ofinfection will die as a result (over 23,000 deaths per year) and inthose who survive, their hospitalization will be prolonged by an averageof 24 days. Complications related to bloodstream infections includecellulites, the formation of abscesses, septic thrombophlebitis, andinfective endocarditis. Therefore, there is a tremendous clinical needto reduce the morbidity and mortality associated with intravascularcatheter infections.

The most common point of entry for the infection-causing bacteria istracking along the device from the insertion site in the skin. Skinflora spread along the outside of the device to ultimately gain accessto the bloodstream. Other possible sources of infection include acontaminated infusate, contamination of the catheter hub-infusion tubingjunction, and hospital personnel. The incidence of infection increasesthe longer the catheter remains in place and any device remaining insitu for more than 72 hours is particularly susceptible. The most commoninfectious agents include common skin flora such as coagulase-negativestaphylococci (S. epidermidis, S. saprophyticus) and Staphylococcusaureus (particularly MRSA—methicillin—resistant S. aureus) which accountfor ⅔ of all infections. Coagulase-negative staphylococci (CNS) is themost commonly isolated organism from the blood of hospitalized patients.CNS infections tend to be indolent; often occurring after a long latentperiod between contamination (i.e. exposure of the medical device to CNSbacteria from the skin during implantation) and the onset of clinicalillness. Unfortunately, most clinically significant CNS infections arecaused by bacterial strains that are resistant to multiple antibiotics,making them particularly difficult to treat. Other organisms known tocause vascular access catheter-related infections include Enterococci(e.g. E. coli, VRE—vancomycin-resistant enterococcci), Gram-negativeaerobic bacilli, Pseudomonas aeruginosa, Klebsiella spp., Serratiamarcescens, Burkholderia cepacia, Citrobacter freundii, Corynebacteriaspp. and Candida species.

Most cases of vascular access catheter-related infection require removalof the catheter and treatment with systemic antibiotics (although fewantibiotics are effective), with vancomycin being the drug of choice. Asmentioned previously, mortality associated with vascular accesscatheter-related infection is high, while the morbidity and costassociated with treating survivors is also extremely significant.

It is therefore extremely important to develop vascular access catheterscapable of reducing the incidence of bloodstream infections. Since it isimpossible to predict in advance which catheters will become infected,any catheter expected to be in place longer than a couple of days wouldbenefit from a therapeutic coating capable of reducing the incidence ofbacterial colonization of the device. An ideal therapeutic coating wouldhave one or more of the following characteristics: (a) the ability tokill, prevent, or inhibit colonization of a wide array of potentialinfectious agents including most or all of the species listed above; (b)the ability to kill, prevent, or inhibit colonization of bacteria (suchas CNS and VRE) that are resistant to multiple antibiotics; (c) utilizea therapeutic agent unlikely to be used in the treatment of abloodstream infection should one develop (i.e., one would not want tocoat the device with a broad-acting antibiotic, for if a strain ofbacteria resistant to the antibiotic were to develop on the device itwould jeopardize systemic treatment of the patient since the infectingagent would be resistant to a potentially useful therapeutic).

Several classes of anticancer agents are particularly suitable forincorporation into coatings for vascular catheters, namely,anthracyclines (e.g., doxorubicin and mitoxantrone), fluoropyrimidines(e.g., 5-FU), folic acid antagonists (e.g., methotrexate), andpodophylotoxins (e.g., etoposide). These agents have a high degree ofantibacterial activity against CNS (S. epidermidis) and Staphylococcusaureus—the most common causes of vascular catheter infections.Particularly preferred agents are doxorubicin, mitoxantrone,5-fluorouracil and analogues and derivatives thereof which also haveactivity against Escheridia coli and Pseudomonas aeruginosa. It isimportant to note that not all anticancer agents are suitable for thepractice of the present invention as several agents, including2-mercaptopurine, 6-mercaptopurine, hydroxyurea, cytarabine,cisplatinum, tubercidin, paclitaxel, and camptothecin did not haveantibacterial activity against the organisms known to cause vascularaccess catheter-related infections.

1. Central Venous Catheters

For the purposes of this invention, the term “Central Venous Catheters”should be understood to include any catheter or line that is used todeliver fluids to the large (central) veins of the body (e.g., jugular,pulmary, femoral, iliac, inferior vena cava, superior vena cava,axillary etc.). Examples of such catheters include central venouscatheters, total parenteral nutrition catheters, peripherally insertedcentral venous catheters, flow-directed balloon-tipped pulmonary arterycatheters, long-term central venous access catheters (such as Hickmanlines and Broviac catheters). Representative examples of such cathetersare described in U.S. Pat. Nos. 3,995,623, 4,072,146 4,096,860,4,099,528, 4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329,4,960,409, 5,176,661, 5,916,208.

As described previously, 55,000 cases of bloodstream infections arecaused by central venous catheters every year in the United Statesresulting in 23,000 deaths. The risk of infection increases the longerthe catheter remains in place, particularly if it is used beyond 72hours. Severe complications of central venous catheter infection alsoinclude infective endocarditis and suppurative phlebitis of the greatveins. If the device becomes infected, it must be replaced at a new site(over-the-wire exchange is not acceptable) which puts the patient atfurther risk to develop mechanical complications of insertion such asbleeding, pneumothorax and hemothorax. In addition, systemic antibiotictherapy is also required. An effective therapy would reduce theincidence of device infection, reduce the incidence of bloodstreaminfection, reduce the mortality rate, reduce the incidence ofcomplications (such as endocarditis or suppurative phlebitis), prolongthe effectiveness of the central venous catheter and/or reduce the needto replace the catheter. This would result in lower mortality andmorbidity for patients with central venous catheters in place.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe vascular catheter. The drug(s) can be applied to the central venouscatheter system in several manners: (a) as a coating applied to theexterior surface of the intravascular portion of the catheter and/or thesegment of the catheter that traverses the skin; (b) as a coatingapplied to the interior and exterior surface of the intravascularportion of the catheter and/or the segment of the catheter thattraverses the skin; (c) incorporated into the polymers which comprisethe intravascular portion of the catheter; (d) incorporated into, orapplied to the surface of, a subcutaneous “cuff” around the catheter;(e) in solution in the infusate; (f) incorporated into, or applied as acoating to, the catheter hub, junctions and/or infusion tubing; and (g)any combination of the aforementioned.

Drug-coating of, or drug incorporation into, the central venous catheterwill allow bacteriocidal drug levels to be achieved locally on thecatheter surface, thus reducing the incidence of bacterial colonizationof the vascular catheter (and subsequent development of blood borneinfection), while producing negligible systemic exposure to the drugs.Although for some agents polymeric carriers are not required forattachment of the drug to the catheter surface, several polymericcarriers are particularly suitable for use in this embodiment. Ofparticular interest are polymeric carriers such as polyurethanes (e.g.,ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylicor methacrylic copolymers (e.g., poly(ethylene-co-acrylic acid),cellulose-derived polymers (e.g. nitrocellulose, Cellulose AcetateButyrate, Cellulose acetate propionate), acrylate and methacrylatecopolymers (e.g., poly(ethylene-co-vinyl acetate)) as well as blendsthereof.

As central venous catheters are made in a variety of configurations andsizes, the exact dose administered will vary with device size, surfacearea and design. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit area (of the portion of the device being coated), totaldrug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the drug to the central venous catheter, thepreferred anticancer agents, used alone or in combination, should beadministered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the device, or applied without a polymer carrier,the total dose of doxorubicin applied to the central venous catheter(and the other components of the infusion system) should not exceed 25mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment,the total amount of drug applied to the central venous catheter (and theother components of the infusion system) should be in the range of 1 μgto 5 mg. The dose per unit area of the device (i.e. the amount of drugas a function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the device surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release doxorubicin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the device surface such that a minimum concentration of10⁻⁷-10⁻⁴ M of doxorubicin is maintained on the device surface. It isnecessary to insure that drug concentrations on the device surfaceexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of thedevice such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-30 days. It should be readily evident giventhe discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the device, or applied without a carrier polymer, the total dose ofmitoxantrone applied to the central venous catheter (and the othercomponents of the infusion system) should not exceed 5 mg (range of 0.01μg to 5 mg). In a particularly preferred embodiment, the total amount ofdrug applied to the central venous catheter (and the other components ofthe infusion system) should be in the range of 0.1 μg to 1 mg. The doseper unit area of the device (i.e. the amount of drug as a function ofthe surface area of the portion of the device to which drug is appliedand/or incorporated) should fall within the range of 0.01 μg-20 μg permm² of surface area. In a particularly preferred embodiment,mitoxantrone should be applied to the device surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe device surface such that a minimum concentration of 10⁻⁵-10⁻⁶ M ofmitoxantrone is maintained on the device surface. It is necessary toinsure that drug concentrations on the device surface exceedconcentrations of mitoxantrone known to be lethal to multiple species ofbacteria and fungi (i.e. are in excess of 10⁻⁵ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, mitoxantrone is released from the surface of the device suchthat anti-infective activity is maintained for a period ranging fromseveral hours to several months. In a particularly preferred embodimentthe drug is released in effective concentrations for a period rangingfrom 1-30 days. It should be readily evident given the discussionsprovided herein that analogues and derivatives of mitoxantrone (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the device, or applied without a carrier polymer,the total dose of 5-fluorouracil applied to the central venous catheter(and the other components of the infusion system) should not exceed 250mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment,the total amount of drug applied to the central venous catheter (and theother components of the infusion system) should be in the range of 10 μgto 25 mg. The dose per unit area of the device (i.e. the amount of drugas a function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of 0.1μg-1 mg per mm² of surface area. In a particularly preferred embodiment,5-fluorouracil should be applied to the device surface at a dose of 1.0μg/mm²-50 μg/mm². As different polymer and non-polymer coatings willrelease 5-fluorouracil at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe device surface such that a minimum concentration of 10⁻⁴-10⁻⁷ M of5-fluorouracil is maintained on the device surface. It is necessary toinsure that drug concentrations on the device surface exceedconcentrations of 5-fluorouracil known to be lethal to numerous speciesof bacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, 5-fluorouracil is released from the surface of the devicesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1-30 days. It should be readily evident given thediscussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the device, or applied without a carrier polymer,the total dose of etoposide applied to the central venous catheter (andthe other components of the infusion system) should not exceed 25 mg(range of 0.1 μg to 25 mg). In a particularly preferred embodiment, thetotal amount of drug applied to the central venous catheter (and theother components of the infusion system) should be in the range of 1 μgto 5 mg. The dose per unit area of the device (i.e. the amount of drugas a function of the surface area of the portion of the device to whichdrug is applied and/or incorporated) should fall within the range of0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the device surface at a doseof 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymer coatingswill release etoposide at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe device surface such that a concentration of 10⁻⁵-10⁻⁶ M of etoposideis maintained on the device surface. It is necessary to insure that drugconcentrations on the device surface exceed concentrations of etoposideknown to be lethal to a variety of bacteria and fungi (i.e., are inexcess of 10⁻⁵ M; although for some embodiments lower drug levels willbe sufficient). In a preferred embodiment, etoposide is released fromthe surface of the device such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1-30 days. It should be readilyevident based upon the discussions provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of thecentral venous catheter coating. Similarly an anthracycline (e.g.,doxorubicin or mitoxantrone), fluoropyrimidine (e.g., 5-fluorouracil),folic acid antagonist (e.g., methotrexate) and/or podophylotoxin (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy. Since thrombogenicity of the catheter isassociated with an increased risk of infection, combinations ofanthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines(e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexateand/or podophylotoxins (e.g., etoposide) can be combined withantithrombotic and/or antiplatelet agents (for example, heparin, dextransulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissueplasminogen activator) to enhance efficacy.

2. Peripheral Intravenous Catheters

For the purposes of this invention, the term “Peripheral VenousCatheters” should be understood to include any catheter or line that isused to deliver fluids to the smaller (peripheral) superficial veins ofthe body.

Peripheral venous catheters have a much lower rate of infection than docentral venous catheters, particularly if they are in place for lessthan 72 hours. One exception is peripheral catheters inserted into thefemoral vein (so called “femoral lines”) which have a significantlyhigher rate of infection. The organisms that cause infections in aperipheral venous catheter are identical to those described above (forcentral venous catheters).

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe peripheral vascular catheter. The drug(s) can be applied to theperipheral venous catheter system in several manners: (a) as a coatingapplied to the exterior and/or interior surface of the intravascularportion of the catheter and/or the segment of the catheter thattraverses the skin; (b) incorporated into the polymers which comprisethe intravascular portion of the catheter; (c) incorporated into, orapplied to the surface of, a subcutaneous “cuff” around the catheter;(e) in solution in the infusate; (f) incorporated into, or applied as acoating to, the catheter hub, junctions and/or infusion tubing; and (g)any combination of the aforementioned.

The formulation and dosing guidelines for this embodiment are identicalto those described for central venous catheters.

3. Arterial Lines and Transducers

Arterial lines are used to draw arterial blood gasses, obtain accurateblood pressure readings and to deliver fluids. They are placed in aperipheral artery (typically the radial artery) and often remain inplace for several days. Arterial lines have a very high rate ofinfection (12-20% of arterial lines become infected) and the causativeorganisms are identical to those described above (for central venouscatheters).

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the arterialline in several manners: (a) as a coating applied to the exterior and/orinterior surface of the intravascular portion of the catheter and/or thesegment of the catheter that traverses the skin; (b) incorporated intothe polymers which comprise the intravascular portion of the catheter;(c) incorporated into, or applied to the surface of, a subcutaneous“cuff” around the catheter; (e) in solution in the infusate; (f)incorporated into, or applied as a coating to, the catheter hub,junctions and/or infusion tubing; and (g) any combination of theaforementioned.

The formulation and dosing guidelines for this embodiment are identicalto those described for central venous catheters.

B. Prosthetic Heart Valve Endocarditis (PVE)

Prosthetic heart valves, mechanical and bioprosthetic, are at asignificant risk for developing an infection. In fact, 3-6% of patientsdevelop valvular infection within 5 years of valve replacement surgeryand prosthetic valve endocarditis accounts for up to 15% of all cases ofendocarditis. The risk of developing an infection is not uniform—therisk is greatest in the first year following surgery with a peakincidence between the second and third month postoperatively. Mechanicalvalves in particular are susceptible to infection in the 3 monthsfollowing surgery and the microbiology is suggestive of nosocomialinfection. Therefore, a drug coating designed to prevent colonizationand infection of the valves in the months following surgery could be ofgreat benefit in the prevention of this important medical problem. Theincidence of prosthetic valve endocarditis has not changed in the last40 years despite significant advances in surgical and sterilizationtechnique.

Representative examples of prosthetic heart valves include thosedescribed in U.S. Pat. Nos. 3,656,185, 4,106,129, 4,892,540, 5,528,023,5,772,694, 6,096,075, 6,176,877, 6,358,278, and 6,371,983

Early after valve implantation, the prosthetic valve sewing ring andannulus are not yet endothelialized. The accumulation of platelets andthrombus at the site provide an excellent location for the adherence andcolonization of microorganisms. Bacteria can be seeded during thesurgical procedure itself or as a result of bacteremia arising in theearly postoperative period (usually contamination from i.v. catheters,catheters to determine cardiac output, mediastinal tubes, chest tubes orwound infections). Common causes of PVE include Coagulase NegativeStaphylococci (Staphylococcus epidermidis; 30%), Staphylococcus aureus(23%), Gram Negative Enterococci (Enterobacteriaceae, Pseudomonasarugenosa; 14%), Fungi (Candida albicans, Aspergillis: 12%), andCorynebacterium diptheriae. PVE of bioprosthetic valves is largelyconfined to the leaflets (and rarely the annulus), whereas the annulusis involved in the majority of cases of PVE in mechanical valves (82%).

Unfortunately, eradication of the infecting organism with antimicrobialtherapy alone is often difficult or impossible. As a result, manypatients who develop this complication require repeat open-heart surgeryto replace the infected valve resulting in significant morbidity andmortality. Even if the infection is successfully treated medically,damage to the leaflets in bioprosthetic valves reduces the lifespan ofthe valve. Particularly problematic are patients who develop aninfection caused by Staphylococcus aureus, as they have a 50-85%mortality rate and overall reoperation rate of 50-65%. Infections causedby Staphylococcus epidermidis are also difficult to treat as themajority are caused by organisms resistant to all currently availablebeta-lactam antibiotics. Other complications of prosthetic valveendocarditis include valve malfunction (stenosis, regurgitation),abscess formation, embolic complications (such as stroke, CNShemorrhage, cerebritis), conduction abnormalities, and death (55-75% ofpatients who develop an infection in the first 2 months after surgery).

An effective therapeutic valve coating would reduce the incidence ofprosthetic valve endocarditis, reduce the mortality rate, reduce theincidence of complications, prolong the effectiveness of the prostheticvalve and/or reduce the need to replace the valve. This would result inlower mortality and morbidity for patients with prosthetic heart valves.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe bioprosthetic or mechanical valve. The drug(s) can be applied to theprosthetic valve in several manners: (a) as a coating applied to thesurface of the annular ring (particularly mechanical valves); (b) as acoating applied to the surface of the valve leaflets (particularlybioprosthetic valves); (c) incorporated into the polymers which comprisethe annular ring; and/or (d) any combination of the aforementioned.

Drug-coating of, or drug incorporation into prosthetic heart valves willallow bacteriocidal drug levels to be achieved locally on the valvularsurface, thus reducing the incidence of bacterial colonization andsubsequent development of PVE, while producing negligible systemicexposure to the drugs. Although for some agents polymeric carriers arenot required for attachment of the drug to the valve annular ring and/orleaflets, several polymeric carriers are particularly suitable for usein this embodiment. Of particular interest are polymeric carriers suchas polyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials],HydroMed640™[CT Biomaterials], HYDROSLIP C™ [CT Biomaterials],HYDROTHANE™ [CT Biomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.,nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.,poly(ethylene-co-vinyl acetate)), as well as blends thereof.

As prosthetic heart valves are made in a variety of configurations andsizes, the exact dose administered will vary with device size, surfacearea and design. However, certain principles can be applied in theapplication of this art. Drug dose can be calculated as a function ofdose per unit area (of the portion of the device being coated), totaldrug dose administered can be measured and appropriate surfaceconcentrations of active drug can be determined. Regardless of themethod of application of the drug to the prosthetic heart valve, thepreferred anticancer agents, used alone or in combination, should beadministered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the prosthetic heart valve, or applied without acarrier polymer, the total dose of doxorubicin applied to the prostheticheart valve should not exceed 25 mg (range of 0.1 μg to 25 mg). In aparticularly preferred embodiment, the total amount of drug applied tothe prosthetic heart valve should be in the range of 1 μg to 5 mg. Thedose per unit area of the valve (i.e., the amount of drug as a functionof the surface area of the portion of the valve to which drug is appliedand/or incorporated) should fall within the range of 0.01 μg-100 μg permm² of surface area. In a particularly preferred embodiment, doxorubicinshould be applied to the valve surface at a dose of 0.1 μg/mm²-10μg/mm². As different polymer and non-polymer coatings will releasedoxorubicin at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from the valvesurface such that a minimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicinis maintained on the surface. It is necessary to insure that drugconcentrations on the valve surface exceed concentrations of doxorubicinknown to be lethal to multiple species of bacteria and fungi (i.e., arein excess of 10⁻⁴ M; although for some embodiments lower concentrationsare sufficient). In a preferred embodiment, doxorubicin is released fromthe surface of the valve such that anti-infective activity is maintainedfor a period ranging from several hours to several months. In aparticularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1-6 months. It should bereadily evident based upon the discussions provided herein thatanalogues and derivatives of doxorubicin (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as doxorubicin isadministered at half the above parameters, a compound half as potent asdoxorubicin is administered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the prosthetic heart valve, or applied without a carrier polymer, thetotal dose of mitoxantrone applied to the prosthetic heart valve shouldnot exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied to the prosthetic heartvalve should be in the range of 0.1 μg to 1 mg. The dose per unit areaof the valve (i.e. the amount of drug as a function of the surface areaof the portion of the valve to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-20 μg per mm² ofsurface area. In a particularly preferred embodiment, mitoxantroneshould be applied to the valve surface at a dose of 0.05 μg/mm²-3μg/mm². As different polymer and non-polymer coatings will releasemitoxantrone at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from the valvesurface such that a minimum concentration of 10⁻⁵-10⁻⁶ M of mitoxantroneis maintained on the valve surface. It is necessary to insure that drugconcentrations on the valve surface exceed concentrations ofmitoxantrone known to be lethal to multiple species of bacteria andfungi (i.e. are in excess of 10⁻⁵ M; although for some embodiments lowerdrug levels will be sufficient). In a preferred embodiment, mitoxantroneis released from the surface of the valve such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1-6months. It should be readily evident based upon the discussions providedherein that analogues and derivatives of mitoxantrone (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the prosthetic heart valve, or applied without acarrier polymer, the total dose of 5-fluorouracil applied to theprosthetic heart valve should not exceed 250 mg (range of 1.0 μg to 250mg). In a particularly preferred embodiment, the total amount of drugapplied to the prosthetic heart valve should be in the range of 10 μg to25 mg. The dose per unit area of the valve (i.e. the amount of drug as afunction of the surface area of the portion of the valve to which drugis applied and/or incorporated) should fall within the range of 0.1 μg-1mg per mm² of surface area. In a particularly preferred embodiment,5-fluorouracil should be applied to the valve surface at a dose of 1.0μg/mm²-50 μg/mm². As different polymer and non-polymer coatings willrelease 5-fluorouracil at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe valve surface such that a minimum concentration of 10⁻⁴-10⁻⁷ M of5-fluorouracil is maintained on the valve surface. It is necessary toinsure that drug concentrations on the prosthetic heart valve surfaceexceed concentrations of 5-fluorouracil known to be lethal to numerousspecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, 5-fluorouracil is released from the surface of thevalve such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-6 months. It should be readily evident basedupon the discussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g., acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the prosthetic heart valve, or applied without acarrier polymer, the total dose of etoposide applied to the prostheticheart valve should not exceed 25 mg (range of 0.1 μg to 25 mg). In aparticularly preferred embodiment, the total amount of drug applied tothe prosthetic heart valve should be in the range of 1 μg to 5 mg. Thedose per unit area of the valve (i.e., the amount of drug as a functionof the surface area of the portion of the valve to which drug is appliedand/or incorporated) should fall within the range of 0.01 μg-100 μg permm² of surface area. In a particularly preferred embodiment, etoposideshould be applied to the prosthetic heart valve surface at a dose of 0.1μg/mm²-100 μg/mm². As different polymer and non-polymer coatings willrelease etoposide at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from thevalve surface such that a concentration of 10⁻⁵-10⁻⁶ M of etoposide ismaintained on the valve surface. It is necessary to insure that drugconcentrations on the valve surface exceed concentrations of etoposideknown to be lethal to a variety of bacteria and fungi (i.e., are inexcess of 10⁻⁵ M; although for some embodiments lower drug levels willbe sufficient). In a preferred embodiment, etoposide is released fromthe surface of the valve such that anti-infective activity is maintainedfor a period ranging from several hours to several months. In aparticularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1-6 months. It should bereadily evident based upon the discussions provided herein thatanalogues and derivatives of etoposide (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as etoposide isadministered at half the above parameters, a compound half as potent asetoposide is administered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theprosthetic heart valve coating. Similarly anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy. Since thrombogenicity of the prostheticheart valve is associated with an increased risk of infection,anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines(e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexateand/or podophylotoxins (e.g., etoposide) can be combined withantithrombotic and/or antiplatelet agents (for example, heparin, dextransulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissueplasminogen activator) to enhance efficacy.

C. Cardiac Pacemaker Infections

Overall, slightly greater than 5% of cardiac pacemakers become infectedfollowing implantation. Cardiac pacemakers are subject to infection intwo general manners: (a) infections involving the pulse generator pocketand/or subcutaneous portion of the lead, and (b) infections involvingthe transvenous intravascular electrode and/or the generator unit.Representative examples of patents which describe pacemakers andpacemaker leads include U.S. Pat. Nos. 4,662,382, 4,782,836, 4,856,521,4,860,751, 5,101,824, 5,261,419, 5,284,491, 6,055,454, 6,370,434, and6,370,434.

The most common type of pacemaker infection involves the subcutaneousgenerator unit or lead wires in the period shortly after placement. Thistype of infection is thought to be the result of contamination of thesurgical site by skin flora at the time of placement. Staphylococcusepidermidis (65-75% of cases), Stapylococcus aureus, Streptococci,Corynebacterium, Proprionibacterium acnes, Enterobacteriaceae andCandida species are frequent causes of this type of infection. Treatmentof the infection at this point is relatively straightforward, theinfected portion of the device is removed, the patient is treated withantibiotics and a new pacemaker is inserted at a different site.Unfortunately, infections of the generator pocket can subsequentlyspread to the epicardial electrodes causing more severe complicationssuch pericarditis, mediastinitis and bacteremia.

Infection of the intravascular portion of the tranvenous electrode posesa more significant clinical problem. This infection is thought to becaused by infection of the subcutaneous portion of the pacing apparatusthat tracks along the device into the intravascular and intracardiacportions of the device. This infection tends to present at a later time(1-6 months post-procedure) and can result in sepsis, endocarditis,pneumonia, bronchitis, pulmonary embolism, cardiac vegetations and evendeath. Coagulase Negative Staphylococci (56% of infections),Staphylococcus aureus (27%), Enterobacteriaceae (6%), Pseudomonasarugenosa (3%) and Candida albicans (2%) are the most common cause ofthis serious form of pacemaker infection. Treatment of this form ofinfection is more complex. The generator and electrodes must be removed(often surgically), antibiotics are required for prolonged periods andan entire new pacemaker system must be inserted. Mortality ratesassociated with this condition can be quite high −41% if treated withantibiotics alone, 20% if treated with electrode removal andantibiotics.

An effective cardiac pacemaker coating would reduce the incidence ofsubcutaneous infection and subsequent tracking of infection to thepericardial and endocardial surfaces of the heart. Clinically, thiswould result in a reduction in the overall rate of infection and reducethe incidence of more severe complications such as sepsis, endocarditis,pneumonia, bronchitis, pulmonary embolism, cardiac vegetations and evendeath. An effective coating could also prolong the effectiveness of thepacemaker and decrease the number of pacemakers requiring replacement,resulting in lower mortality and morbidity for patients with theseimplants.

In a preferred embodiment, an anthracycline (e.g., doxorubicin andmitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist(e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) isformulated into a coating applied to the surface of the components ofthe cardiac pacemaker. The drug(s) can be applied to the pacemaker inseveral manners: (a) as a coating applied to the surface of thegenerator unit; (b) as a coating applied to the surface of thesubcutaneous portion of the lead wires; (c) incorporated into, orapplied to the surface of, a subcutaneous “cuff” around the subcutaneousinsertion site; (d) as a coating applied to the surface of theepicardial electrodes; (e) as a coating applied to the surface of thetransvenous electrode; and/or (f) any combination of the aforementioned.

Drug-coating of, or drug incorporation into cardiac pacemakers willallow bacteriocidal drug levels to be achieved locally on the pacemakersurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug to thegenerator unit, leads and electrodes, several polymeric carriers areparticularly suitable for use in this embodiment. Of particular interestare polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As cardiac pacemakers are made in a variety of configurations and sizes,the exact dose administered will vary with device size, surface area,design and portions of the pacemaker coated. However, certain principlescan be applied in the application of this art. Drug dose can becalculated as a function of dose per unit area (of the portion of thedevice being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the cardiacpacemaker, the preferred anticancer agents, used alone or incombination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the pacemaker components, or applied without acarrier polymer, the total dose of doxorubicin applied to the pacemakershould not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularlypreferred embodiment, the total amount of drug applied should be in therange of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drugas a function of the surface area of the portion of the pacemaker towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the pacemaker surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release doxorubicin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the pacemaker surface such that a minimum concentration of10⁻⁷-10⁻⁴ M of doxorubicin is maintained on the surface. It is necessaryto insure that surface drug concentrations exceed concentrations ofdoxorubicin known to be lethal to multiple species of bacteria and fungi(i.e., are in excess of 10⁻⁴ M; although for some embodiments lowerconcentrations are sufficient). In a preferred embodiment, doxorubicinis released from the surface of the pacemaker such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1 week-6months. It should be readily evident based upon the discussions providedherein that analogues and derivatives of doxorubicin (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asdoxorubicin is administered at half the above parameters, a compoundhalf as potent as doxorubicin is administered at twice the aboveparameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the pacemaker, or applied without a carrier polymer, the total doseof mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 0.1 μg to 1 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the pacemaker to which drug is applied and/or incorporated)should fall within the range of 0.01 μg-20 μg per mm² of surface area.In a particularly preferred embodiment, mitoxantrone should be appliedto the pacemaker surface at a dose of 0.05 μg/mm²-3 μg/mm². As differentpolymer and non-polymer coatings will release mitoxantrone at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the pacemaker surface such that aminimum concentration of 10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. Itis necessary to insure that drug concentrations on the pacemaker surfaceexceed concentrations of mitoxantrone known to be lethal to multiplespecies of bacteria and fungi (i.e. are in excess of 10⁻⁵ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, mitoxantrone is released from the surface of thepacemaker such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of mitoxantrone (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as mitoxantrone is administered at halfthe above parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the pacemaker, or applied without a carrierpolymer, the total dose of 5-fluorouracil applied should not exceed 250mg (range of 1.0 μg to 250 mg). In a particularly preferred embodiment,the total amount of drug applied should be in the range of 10 μg to 25mg. The dose per unit area (i.e. the amount of drug as a function of thesurface area of the portion of the pacemaker to which drug is appliedand/or incorporated) should fall within the range of 0.1 μg-1 mg per mm²of surface area. In a particularly preferred embodiment, 5-fluorouracilshould be applied to the pacemaker surface at a dose of 1.0 μg/mm²-50μg/mm². As different polymer and non-polymer coatings will release5-fluorouracil at differing rates, the above dosing parameters should beutilized in combination with the release rate of the drug from thepacemaker surface such that a minimum concentration of 10⁻⁴-10⁻⁷ M of5-fluorouracil is maintained. It is necessary to insure that surfacedrug concentrations exceed concentrations of 5-fluorouracil known to belethal to numerous species of bacteria and fungi (i.e., are in excess of10⁻⁴ M; although for some embodiments lower drug levels will besufficient). In a preferred embodiment, 5-fluorouracil is released fromthe pacemaker surface such that anti-infective activity is maintainedfor a period ranging from several hours to several months. In aparticularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident based upon the discussions provided herein thatanalogues and derivatives of 5-fluorouracil (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as 5-fluorouracil isadministered at half the above parameters, a compound half as potent as5-fluorouracil is administered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the cardiac pacemaker, or applied without acarrier polymer, the total dose of etoposide applied should not exceed25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the pacemaker to whichdrug is applied and/or incorporated) should fall within the range of0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the pacemaker surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release etoposide at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the pacemaker surface such that a concentration of10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insure thatsurface drug concentrations exceed concentrations of etoposide known tobe lethal to a variety of bacteria and fungi (i.e. are in excess of 10⁻⁵M; although for some embodiments lower drug levels will be sufficient).In a preferred embodiment, etoposide is released from the surface of thepacemaker such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of thepacemaker coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)can be combined with traditional antibiotic and/or antifungal agents toenhance efficacy. Since thrombogenicity of the intravascular portion ofthe transvenous electrode is associated with an increased risk ofinfection, anthracyclines (e.g., doxorubicin or mitoxantrone),fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g.,methotrexate and/or podophylotoxins (e.g., etoposide) can be combinedwith antithrombotic and/or antiplatelet agents (for example heparin,dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissueplasminogen activator) to enhance efficacy.

D. Infections of Implantable Cardioverter-Defibrillators (ICD)

Overall, approximately 5-10% of implantable cardioverter-defibrillatorsbecome infected following implantation (the rate is highest if surgicalplacement is required). Like cardiac pacemakers, implantabledefibrillators are subject to infection in two general manners: (a)infections involving the subcutaneous portion of the device(subcutaneous electrodes and pulse generator unit, and (b) infectionsinvolving the intrathoracic components (rate sensing electrode, SVC coilelectrode and epicardial electrodes). Representative examples of ICD'sand associated components are described in U.S. Pat. Nos. 3,614,954,3,614,955, 4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953,5,776,165, 6,067,471, 6,169,923, and 6,152,955.

Most infections present period shortly after placement and are thoughtto be the result of contamination of the surgical site by skin flora.Staphylococcus epidermidis, Stapylococcus aureus, Streptococci,Corynebacterium, Proprionibacterium acnes, Enterobacteriaceae andCandida species are frequent causes of this type of infection.Unfortunately, treatment frequently involves removal of the entiresystem and prolonged antibiotic therapy.

An effective ICD coating would reduce the incidence of infection-relatedside effects such subcutaneous infection, sepsis and pericarditis. Aneffective coating could also prolong the effectiveness of the ICD anddecrease the number of patients requiring replacement, resulting inlower mortality and morbidity associated with these implants.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe components of the ICD. The drug(s) can be applied in severalmanners: (a) as a coating applied to the surface of the pulse generatorunit; (b) as a coating applied to the surface of the subcutaneousportion of the lead wires; (c) incorporated into, or applied to thesurface of, a subcutaneous “cuff” around the subcutaneous insertionsite; (d) as a coating applied to the surface of the SVC coil electrode;(e) as a coating applied to the surface of the epicardial electrode;and/or (f) any combination of the aforementioned.

Drug-coating of, or drug incorporation into prosthetic heart valves willallow bacteriocidal drug levels to be achieved locally on the ICDsurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug to thegenerator unit, leads and electrodes, several polymeric carriers areparticularly suitable for use in this embodiment. Of particular interestare polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As implantable cardioverter-defibrillators have many design featuressimilar to those found in cardiac pacemakers, the dosing guidelines fordoxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating ICDsare identical to those described above for cardiac pacemakers.

E. Vascular Graft Infections

Infection rates for synthetic vascular grafts range from 1-5% and arehighest in grafts that traverse the inguinal region (such asaorto-femoral grafts and femoral-popliteal grafts). Although infectioncan result from extension of an infection from an adjacent contaminatedtissue or hematogenous seeding, the most common cause of infection isintraoperative contamination. In fact, more than half of all casespresent within the first 3 months after surgery. The most common causesof infection include Staphylococcus aureus (25-35% of cases),Enterobacteriaceae, Pseudomonas aerugenosa, and Coagulase NegativeStaphylococci.

Complications arising from vascular graft infection include sepsis,subcutaneous infection, false aneurysm formation, graft thrombosis,haemorrhage, septic or thrombotic emboli and graft thrombosis. Treatmentrequires removal of the graft in virtually all cases combined withsystemic antibiotics. Often the surgery must be performed in a stagedmanner (complete resection of the infected graft, debridement ofadjacent infected tissues, development of a healthy arterial stump,reperfusion through an uninfected pathway) further adding to themorbidity and mortality associated with this condition. For example, ifan aortic graft becomes infected there is a 37% mortality rate and a 21%rate of leg amputation in survivors; for infrainguinal grafts the ratesare 18% and 40% respectively.

Representative examples of vascular grafts are described in U.S. Pat.Nos. 3,096,560, 3,805,301, 3,945,052, 4,140,126, 4,323,525, 4,355,426,4,475,972, 4,530,113, 4,550,447, 4,562,596, 4,601,718, 4,647,416,4,878,908, 5,024,671, 5,104,399, 5,116,360, 5,151,105, 5,197,977,5,282,824, 5,405,379, 5,609,624, 5,693,088, and 5,910,168.

An effective vascular graft coating would reduce the incidence ofcomplications such as sepsis, haemorrhage, thrombosis, embolism,amputation and even death. An effective coating would also decrease thenumber of vascular grafts requiring replacement, resulting in lowermortality and morbidity for patients with these implants.

In a preferred embodiment, an anthracycline (e.g., doxorubicin andmitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist(e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) isformulated into a coating applied to the surface of the components ofthe vascular graft. The drug(s) can be applied in several manners: (a)as a coating applied to the external surface of the graft; (b) as acoating applied to the internal (luminal) surface of the graft; and/or(c) as a coating applied to all or parts of both surfaces.

Drug-coating of, or drug incorporation into vascular grafts will allowbacteriocidal drug levels to be achieved locally on the graft surface,thus reducing the incidence of bacterial colonization and subsequentdevelopment of infectious complications, while producing negligiblesystemic exposure to the drugs. Although for some agents polymericcarriers are not required for attachment of the drug, several polymericcarriers are particularly suitable for use in this embodiment. Ofparticular interest are polymeric carriers such as polyurethanes (e.g.,ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylicor methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid),cellulose-derived polymers (e.g. nitrocellulose, Cellulose AcetateButyrate, Cellulose acetate propionate), acrylate and methacrylatecopolymers (e.g. poly(ethylene-co-vinyl acetate)) collagen as well asblends thereof.

As vascular grafts are made in a variety of configurations and sizes,the exact dose administered will vary with device size, surface area,design and portions of the graft coated. However, certain principles canbe applied in the application of this art. Drug dose can be calculatedas a function of dose per unit area (of the portion of the device beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the vascular graft, thepreferred anticancer agents, used alone or in combination, should beadministered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the vascular graft components (such as Dacron orTeflon), or applied without a carrier polymer, the total dose ofdoxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg).In a particularly preferred embodiment, the total amount of drug appliedshould be in the range of 1 μg to 5 mg. The dose per unit area (i.e. theamount of drug as a function of the surface area of the portion of thevascular graft to which drug is applied and/or incorporated) should fallwithin the range of 0.01 μg-100 μg per mm² of surface area. In aparticularly preferred embodiment, doxorubicin should be applied to thevascular graft surface at a dose of 0.1 μg/mm²-10 μg/mm². As differentpolymer and non-polymer coatings will release doxorubicin at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the vascular graft surface suchthat a minimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintainedon the surface. It is necessary to insure that surface drugconcentrations exceed concentrations of doxorubicin known to be lethalto multiple species of bacteria and fungi (i.e., are in excess of 10⁻⁴M; although for some embodiments lower concentrations are sufficient).In a preferred embodiment, doxorubicin is released from the surface ofthe vascular graft such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of doxorubicin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as doxorubicin is administered at halfthe above parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the vascular graft (such as Dacron or Teflon), or applied without acarrier polymer, the total dose of mitoxantrone applied should notexceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the vascular graft towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-μg per mm² of surface area. In a particularly preferredembodiment, mitoxantrone should be applied to the vascular graft surfaceat a dose of 0.05 μg/mm²-3 μg/mm². As different polymer and non-polymercoatings will release mitoxantrone at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the vascular graft surface such that a minimumconcentration of 10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It isnecessary to insure that drug concentrations on the surface exceedconcentrations of mitoxantrone known to be lethal to multiple species ofbacteria and fungi (i.e. are in excess of 10⁻⁵ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, mitoxantrone is released from the vascular graft surfacesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1 week-6 months. It should be readily evident based uponthe discussions provided herein that analogues and derivatives ofmitoxantrone (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as mitoxantrone is administered at half theabove parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the vascular graft (such as Dacron or Teflon), orapplied without a carrier polymer, the total dose of 5-fluorouracilapplied should not exceed 250 mg (range of 1.0 μg to 250 mg). In aparticularly preferred embodiment, the total amount of drug appliedshould be in the range of 10 μg to 25 mg. The dose per unit area (i.e.the amount of drug as a function of the surface area of the portion ofthe vascular graft to which drug is applied and/or incorporated) shouldfall within the range of 0.1 μg-1 mg per mm² of surface area. In aparticularly preferred embodiment, 5-fluorouracil should be applied tothe vascular graft surface at a dose of 1.0 μg/mm²-50 μg/mm². Asdifferent polymer and non-polymer coatings will release 5-fluorouracilat differing rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the vascular graftsurface such that a minimum concentration of 10⁻⁴-10⁻⁷ M of5-fluorouracil is maintained. It is necessary to insure that surfacedrug concentrations exceed concentrations of 5-fluorouracil known to belethal to numerous species of bacteria and fungi (i.e., are in excess of10⁻⁴ M; although for some embodiments lower drug levels will besufficient). In a preferred embodiment, 5-fluorouracil is released fromthe vascular graft surface such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident based upon the discussions provided herein thatanalogues and derivatives of 5-fluorouracil (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as 5-fluorouracil isadministered at half the above parameters, a compound half as potent as5-fluorouracil is administered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the vascular graft (such as Dacron or Teflon), orapplied without a carrier polymer, the total dose of etoposide appliedshould not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularlypreferred embodiment, the total amount of drug applied should be in therange of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drugas a function of the surface area of the portion of the vascular graftto which drug is applied and/or incorporated) should fall within therange of 0.01 μg-100 μg per mm² of surface area. In a particularlypreferred embodiment, etoposide should be applied to the vascular graftsurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release etoposide at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the vascular graft surface such that aconcentration of 10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessaryto insure that surface drug concentrations exceed concentrations ofetoposide known to be lethal to a variety of bacteria and fungi (i.e.are in excess of 10⁻⁵ M; although for some embodiments lower drug levelswill be sufficient). In a preferred embodiment, etoposide is releasedfrom the surface of the vascular graft such that anti-infective activityis maintained for a period ranging from several hours to several months.In a particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident based upon the discussions provided herein thatanalogues and derivatives of etoposide (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as etoposide isadministered at half the above parameters, a compound half as potent asetoposide is administered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of thevascular graft coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate and/or podophylotoxins (e.g., etoposide)can be combined with traditional antibiotic and/or antifungal agents toenhance efficacy. Since thrombogenicity of the vascular graft isassociated with an increased risk of infection, anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,etoposide) can be combined with antithrombotic and/or antiplateletagents (for example heparin, dextran sulphate, danaparoid, lepirudin,hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone,indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost,ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban,streptokinase, and/or tissue plasminogen activator) to enhance efficacy.

F. Infections Associated with Ear, Nose and Throat Implants

Bacterial infections involving the ear, nose and throat are commonoccurrences in both children and adults. For the management of chronicobstruction secondary to persistent infection, the use of implantedmedical tubes is a frequent form of treatment. Specifically, chronicotitis media is often treated with the surgical implantation oftympanostomy tubes and chronic sinusitis is frequently treated withsurgical drainage and the placement of a sinus stent.

Tympanostomy Tubes

Acute otitis media is the most common bacterial infection, the mostfrequent indication for surgical therapy, the leading cause of hearingloss and a common cause of impaired language development in children.The cost of treating this condition in children under the age of five isestimated at $5 billion annually in the United States alone. In fact,85% of all children will have at least one episode of otitis media and600,000 will require surgical therapy annually. The prevalence of otitismedia is increasing and for severe cases surgical therapy is more costeffective than conservative management.

Acute otitis media (bacterial infection of the middle ear) ischaracterized by Eustachian tube dysfunction leading to failure of themiddle ear clearance mechanism. The most common causes of otitis mediaare Streptococcus pneumoniae (30%), Haemophilus influenza (20%),Branhamella catarrhalis (12%), Streptococcus pyogenes (3%), andStaphylococcus aureus (1.5%). The end result is the accumulation ofbacteria, white blood cells and fluid which, in the absence of anability to drain through the Eustachian tube, results in increasedpressure in the middle ear. For many cases antibiotic therapy issufficient treatment and the condition resolves. However, for asignificant number of patients the condition becomes frequentlyrecurrent or does not resolve completely. In recurrent otitis media orchronic otitis media with effusion, there is a continuous build-up offluid and bacteria that creates a pressure gradient across the tympanicmembrane causing pain and impaired hearing. Fenestration of the tympanicmembrane (typically with placement of a tympanostomy tube) relieves thepressure gradient and facilitates drainage of the middle ear (throughthe outer ear instead of through the Eustachian tube—a form of“Eustachian tube bypass”).

Surgical placement of tympanostomy tubes is the most widely usedtreatment for chronic otitis media because, although not curative, itimproves hearing (which in turn improves language development) andreduces the incidence of acute otitis media. Tympanostomy tube placementis one of the most common surgical procedures in the United States with1.3 million surgical placements per year. Nearly all younger childrenand a large percentage of older children require general anaesthesia forplacement. Since general anaesthesia has a higher incidence ofsignificant side effects in children (and represents the single greatestrisk and cost associated with the procedure), it is desirable to limitthe number of anaesthetics that the child is exposed to. Commoncomplications of tympanostomy tube insertion include chronic otorrhea(often due to infection by S. pneumoniae, H. influenza, Pseudomonasaerugenosa, S. aureus, or Candida), foreign body reaction with theformation of granulation tissue and infection, plugging (usuallyobstructed by granulation tissue, bacteria and/or clot), tympanicmembrane perforation, myringosclerosis, tympanic membrane atrophy(retraction, atelectasis), and cholesteatoma.

An effective tympanostomy tube coating would allow easy insertion,remain in place for as long as is required, be easily removed in theoffice without anaesthesia, resist infection and prevent the formationof granulation tissue in the tube (which can not only lead toobstruction, but also “tack down” the tube such that surgical removal ofthe tube under anaesthetic becomes necessary). An effective tympanostomytube would also reduce the incidence of complications such as chronicotorrhea (often due to infection by S. pneumoniae, H. influenza,Pseudomonas aerugenosa, S. aureus, or Candida); maintain patency(prevent obstruction by granulation tissue, bacteria and/or clot);and/or reduce tympanic membrane perforation, myringosclerosis, tympanicmembrane atrophy and cholesteatoma. Therefore, development of a tubewhich does not become obstructed by granulation tissue, does not scar inplace and is less prone to infection (thereby reducing the need toremove/replace the tube) would be a significant medical advancement.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe tympanostomy tube. The drug(s) can be applied in several manners:(a) as a coating applied to the external surface of the tympanostomytube; (b) as a coating applied to the internal (luminal) surface of thetympanostomy tube; (c) as a coating applied to all or parts of bothsurfaces; and/or (d) incorporated into the polymers which comprise thetympanostomy tube.

Drug-coating of, or drug incorporation into, the tympanostomy tube willallow bacteriocidal drug levels to be achieved locally on the tubesurface, thus reducing the incidence of bacterial colonization (andsubsequent development of middle ear infection), while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug to thetympanostomy tube surface, several polymeric carriers are particularlysuitable for use in this embodiment. Of particular interest arepolymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CTBiomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

There are two general designs of tympanostomy tubes: grommet-shapedtubes, which tend to stay in place for less than 1 year but have a lowincidence of permanent perforation of the tympanic membrane (1%), andT-tubes, which stay in place for several years but have a higher rate ofpermanent perforation (5%). As tympanostomy tubes are made in a varietyof configurations and sizes, the exact dose administered will vary withdevice size, surface area and design. However, certain principles can beapplied in the application of this art. Drug dose can be calculated as afunction of dose per unit area (of the portion of the device beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the tympanostomy tube, thepreferred anticancer agents, used alone or in combination, should beadministered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the tympanostomy tube components, or appliedwithout a carrier polymer, the total dose of doxorubicin applied shouldnot exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the tympanostomy tube towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the tympanostomy tubesurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release doxorubicin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the tympanostomy tube surface such that aminimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on thesurface. It is necessary to insure that surface drug concentrationsexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of thetympanostomy tube such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentbased upon the discussions provided herein that analogues andderivatives of doxorubicin (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as doxorubicin is administered at halfthe above parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the tympanostomy tube, or applied without a carrier polymer, thetotal dose of mitoxantrone applied should not exceed 5 mg (range of 0.01μg to 5 mg). In a particularly preferred embodiment, the total amount ofdrug applied should be in the range of 0.1 μg to 1 mg. The dose per unitarea (i.e. the amount of drug as a function of the surface area of theportion of the tympanostomy tube to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-20 μg per mm² ofsurface area. In a particularly preferred embodiment, mitoxantroneshould be applied to the tympanostomy tube surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe tympanostomy tube surface such that a minimum concentration of10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It is necessary to insurethat drug concentrations on the surface exceed concentrations ofmitoxantrone known to be lethal to multiple species of bacteria andfungi (i.e. are in excess of 10⁻⁵ M; although for some embodiments lowerdrug levels will be sufficient). In a preferred embodiment, mitoxantroneis released from the tympanostomy tube surface such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1 week-6months. It should be readily evident based upon the discussions providedherein that analogues and derivatives of mitoxantrone (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the tympanostomy tube, or applied without acarrier polymer, the total dose of 5-fluorouracil applied should notexceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the tympanostomy tube towhich drug is applied and/or incorporated) should fall within the rangeof 0.1 μg-1 mg per mm² of surface area. In a particularly preferredembodiment, 5-fluorouracil should be applied to the tympanostomy tubesurface at a dose of 1.0 μg/mm²-50 μg/mm². As different polymer andnon-polymer coatings will release 5-fluorouracil at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the tympanostomy tube surface such that aminimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. Itis necessary to insure that surface drug concentrations exceedconcentrations of 5-fluorouracil known to be lethal to numerous speciesof bacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, 5-fluorouracil is released from the tympanostomy tubesurface such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the tympanostomy tube, or applied without acarrier polymer, the total dose of etoposide applied should not exceed25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the tympanostomy tube towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the tympanostomy tube surfaceat a dose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release etoposide at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the tympanostomy tube surface such that a concentration of10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insure thatsurface drug concentrations exceed concentrations of etoposide known tobe lethal to a variety of bacteria and fungi (i.e. are in excess of 10⁻⁵M; although for some embodiments lower drug levels will be sufficient).In a preferred embodiment, etoposide is released from the surface of thetympanostomy tube such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofetoposide (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as etoposide is administered at half the aboveparameters, a compound half as potent as etoposide is administered attwice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of thetympanostomy tube coating. Similarly anthracyclines (e.g., doxorubicinor mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy.

Sinus Stents

The sinuses are four pairs of hollow regions contained in the bones ofthe skull named after the bones in which they are located (ethmoid,maxillary, frontal and sphenoid). All are lined by respiratory mucosawhich is directly attached to the bone. Following an inflammatory insultsuch as an upper respiratory tract infection or allergic rhinitis, apurulent form of sinusitis can develop. Occasionally secretions can beretained in the sinus due to altered ciliary function or obstruction ofthe opening (ostea) that drains the sinus. Incomplete drainage makes thesinus prone to infection typically with Haemophilus influenza,Streptococcus pneumoniae, Moraxella catarrhalis, Veillonella,Peptococcus, Corynebacterium acnes and certain species of fungi.

When initial treatment such as antibiotics, intranasal steroid spraysand decongestants are ineffective, it may become necessary to performsurgical drainage of the infected sinus. Surgical therapy often involvesdebridement of the ostea to remove anatomic obstructions and removal ofparts of the mucosa. Occasionally a stent (a cylindrical tube whichphysically holds the lumen of the ostea open) is left in the osta toensure drainage is maintained even in the presence of postoperativeswelling. Stents, typically made of stainless steel or plastic, remainin place for several days or several weeks before being removed.

Unfortunately, the stents can become infected or overgrown bygranulation tissue that renders them ineffective. An effective sinusstent coating would allow easy insertion, remain in place for as long asis required, be easily removed in the office without anaesthesia, resistinfection and prevent the formation of granulation tissue in the stent(which can not only lead to obstruction, but also “tack down” the stentsuch that surgical removal becomes necessary). Therefore, development ofa sinus stent which does not become obstructed by granulation tissue,does not scar in place and is less prone to infection would bebeneficial.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe sinus stent. The drug(s) can be applied in several manners: (a) as acoating applied to the external surface of the sinus stent; (b) as acoating applied to the internal (luminal) surface of the sinus stent;(c) as a coating applied to all or parts of both surfaces; and/or (d)incorporated into the polymers which comprise the sinus stent.

Drug-coating of, or drug incorporation into, the sinus stent will allowbacteriocidal drug levels to be achieved locally on the tube surface,thus reducing the incidence of bacterial colonization (and subsequentdevelopment of sinusitis), while producing negligible systemic exposureto the drugs. Although for some agents polymeric carriers are notrequired for attachment of the drug to the sinus stent surface, severalpolymeric carriers are particularly suitable for use in this embodiment.Of particular interest are polymeric carriers such as polyurethanes(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CTBiomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As sinus stents are prone to the same complications and infections fromthe same bacteria, the dosing guidelines for doxorubicin, mitoxantrone,5-fluorouracil and etoposide in coating sinus stents are identical tothose described above for tympanostomy tubes.

G. Infections Associated with Urological Implants

Implanted medical devices are used in the urinary tract with greaterfrequency than in any other body system and have some of the highestrates of infection. In fact, the great majority of urinary devicesbecome infected if they remain in place for a prolonged period of timeand are the most common cause of nosocomial infection.

Urinary (Foley) Catheters

Four-to-five million bladder catheters are inserted into hospitalizedpatients every year in the United States. The duration ofcatheterization is the important risk factor for patients developing aclinically significant infection—the rate of infection increases 5-10%per day that the patient is catheterized. Although simple cystitis canbe treated with a short course of antibiotics (with or without removalof the catheter), serious complications are frequent and can beextremely serious. The infection can ascend to the kidneys causing acutepyelonephritis which can result in scarring and long term kidney damage.Perhaps of greatest concern is the 1-2% risk of developing gram negativesepsis (the risk is 3-times higher in catheterized patients and accountsfor 30% of all cases) which can be extremely difficult to treat and canresult in septic shock and death (up to 50% of patients). Therefore,there exists a significant medical need to produce improved urinarycatheters capable of reducing the incidence of urinary tract infectionin catheterized patients.

The most common cause of infection is bacteria typically found in thebowel or perineum that are able to track up the catheter to gain accessto the normally sterile bladder. Bacteria can be carried into thebladder as the catheter is inserted, gain entry via the sheath ofexudates that surrounds the catheter, and/or travel intraluminallyinside the catheter tubing. Several species of bacteria are able toadhere to the catheter and form a biofilm that provides a protected sitefor growth. With short-term catheterization, single organism infectionsare most common and are typically due to Escherichia coli, Enterococci,Pseudomonas aeruginosa, Klebsiella, Proteus, Enterobacter,Staphylococcus epidermidis, Staphylococcus aureus and Staphylococcussaprophyticus. Patients who are catheterized for long periods of timeare prone to polymicrobial infections caused by all of the organismspreviously mentioned as well as Providencia stuartii, Morganellamorganii and Candida. Antibiotic use either systemically or locally hasbeen largely proven to be ineffective as it tends to result only in theselection of drug-resistant bacteria.

An effective urinary catheter coating would allow easy insertion intothe bladder, resist infection and prevent the formation of biofilm inthe catheter. An effective coating would prevent or reduce the incidenceof urinary tract infection, pyelonephritis, and/or sepsis. In apreferred embodiment, doxorubicin, mitoxantrone, 5-fluorouracil and/oretoposide are formulated into a coating applied to the surface of theurinary catheter. The drug(s) can be applied in several manners: (a) asa coating applied to the external surface of the urinary catheter; (b)as a coating applied to the internal (luminal) surface of the urinarycatheter; (c) as a coating applied to all or parts of both surfaces;and/or (d) incorporated into the polymers which comprise the urinarycatheter.

Drug-coating of, or drug incorporation into, the urinary catheter willallow bacteriocidal drug levels to be achieved locally on the cathetersurface, thus reducing the incidence of bacterial colonization (andsubsequent development of urinary tract infection and bacteremia), whileproducing negligible systemic exposure to the drugs. Although for someagents polymeric carriers are not required for attachment of the drug tothe urinary catheter surface, several polymeric carriers areparticularly suitable for use in this embodiment. Of particular interestare polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As urinary catheters (e.g. Foley catheters, suprapubic catheters) aremade in a variety of configurations and sizes, the exact doseadministered will vary with device size, surface area and design.However, certain principles can be applied in the application of thisart. Drug dose can be calculated as a function of dose per unit area (ofthe portion of the device being coated), total drug dose administeredcan be measured and appropriate surface concentrations of active drugcan be determined. Regardless of the method of application of the drugto the urinary catheter, the preferred anticancer agents, used alone orin combination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the urinary catheter components, or appliedwithout a carrier polymer, the total dose of doxorubicin applied shouldnot exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the urinary catheter towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the urinary cathetersurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release doxorubicin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the urinary catheter surface such that aminimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on thesurface. It is necessary to insure that surface drug concentrationsexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of theurinary catheter such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 hour-1 month. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the urinary catheter, or applied without a carrier polymer, the totaldose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to5 mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 0.1 μg to 1 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the urinary catheter to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-20 μg per mm² ofsurface area. In a particularly preferred embodiment, mitoxantroneshould be applied to the urinary catheter surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe urinary catheter surface such that a minimum concentration of10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It is necessary to insurethat drug concentrations on the surface exceed concentrations ofmitoxantrone known to be lethal to multiple species of bacteria andfungi (i.e. are in excess of 10⁻⁵ M; although for some embodiments lowerdrug levels will be sufficient). In a preferred embodiment, mitoxantroneis released from the urinary catheter surface such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1 hour-1month. It should be readily evident given the discussions providedherein that analogues and derivatives of mitoxantrone (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the urinary catheter, or applied without acarrier polymer, the total dose of 5-fluorouracil applied should notexceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the urinary catheter towhich drug is applied and/or incorporated) should fall within the rangeof 0.1 μg-1 mg per mm² of surface area. In a particularly preferredembodiment, 5-fluorouracil should be applied to the urinary cathetersurface at a dose of 1.0 μg/mm²-50 μg/mm². As different polymer andnon-polymer coatings will release 5-fluorouracil at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the urinary catheter surface such that aminimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. Itis necessary to insure that surface drug concentrations exceedconcentrations of 5-fluorouracil known to be lethal to numerous speciesof bacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, 5-fluorouracil is released from the urinary catheter surfacesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1 hour-1 month. It should be readily evident given thediscussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the urinary catheter, or applied without acarrier polymer, the total dose of etoposide applied should not exceed25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the urinary catheter towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the urinary catheter surfaceat a dose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release etoposide at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the urinary catheter surface such that a concentration of10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insure thatsurface drug concentrations exceed concentrations of etoposide known tobe lethal to a variety of bacteria and fungi (i.e. are in excess of 10⁻⁵M; although for some embodiments lower drug levels will be sufficient).In a preferred embodiment, etoposide is released from the surface of theurinary catheter such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 hour-1 month. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofetoposide (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as etoposide is administered at half the aboveparameters, a compound half as potent as etoposide is administered attwice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theurinary catheter coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate) and podophylotoxins (e.g., etoposide)can be combined with traditional antibiotic and/or antifungal agents toenhance efficacy.

Ureteral Stents

Ureteral stents are hollow tubes with holes along the sides and coils ateither end to prevent migration. Ureteral stents are used to relieveobstructions (caused by stones or malignancy), to facilitate the passageof stones, or to allow healing of ureteral anastomoses or leaksfollowing surgery or trauma. They are placed endoscopically via thebladder or percutaneously via the kidney. A microbial biofilm forms onup to 90% of ureteral stents and 30% develop significant bacteruria withthe incidence increasing the longer the stent is in place. Pseudomonasaeruginosa is the most common pathogen, but Enterococci, Staphylococcusaureus and Candida also cause infection. Effective treatment frequentlyrequires stent removal in addition to antibiotic therapy.

Unfortunately, ureteral stents can become infected or encrusted withurinary salts that render them ineffective. An effective ureteral stentcoating would allow easy insertion, remain in place for as long as isrequired, be easily removed, resist infection and prevent the formationof urinary salts. Therefore, development of a ureteral stent which doesnot become obstructed by granulation tissue, does not scar in place andis less prone to infection would be beneficial.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe ureteral stent. The drug(s) can be applied in several manners: (a)as a coating applied to the external surface of the ureteral stent; (b)as a coating applied to the internal (luminal) surface of the ureteralstent; (c) as a coating applied to all or parts of both surfaces; and/or(d) incorporated into the polymers which comprise the ureteral stent.

Drug-coating of, or drug incorporation into, the ureteral stent willallow bacteriocidal drug levels to be achieved locally on the stentsurface, thus reducing the incidence of bacterial colonization (andsubsequent development of pyelonephritis and/or bacteremia), whileproducing negligible systemic exposure to the drugs. Although for someagents polymeric carriers are not required for attachment of the drug tothe ureteral stent surface, several polymeric carriers are particularlysuitable for use in this embodiment. Of particular interest arepolymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CTBiomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As ureteral stents are prone to the same complications and infectionsfrom the same bacteria, the dosing guidelines for doxorubicin,mitoxantrone, 5-fluorouracil and etoposide in coating ureteral stentsare identical to those described above for urinary catheters. However,unlike the formulations described for urinary catheters, drug releaseshould occur over a 2 to 24 week period.

Urethral Stents

Urethral stents are used for the treatment of recurrent urethralstrictures, detruso-external sphincter dyssynergia and bladder outletobstruction due to benign prostatic hypertrophy. The stents aretypically self-expanding and composed of metal superalloy, titanium,stainless steel or polyurethane. Infections are most often due toCoagulase Negative Staphylococci, Pseudomonas aeruginosa, Enterococci,Staphylococcus aureus, Serratia and Candida. Treatment of infectedstents frequently requires systemic antibiotic therapy and removal ofthe device.

An effective urethral stent coating would allow easy insertion, remainin place for as long as is required, be easily removed, resist infectionand prevent the formation of urinary salts. Therefore, development of aurethral stent which does not become obstructed by granulation tissue,does not scar in place and is less prone to infection would bebeneficial.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe urethral stent. The drug(s) can be applied in several manners: (a)as a coating applied to the external surface of the urethral stent; (b)as a coating applied to the internal (luminal) surface of the urethralstent; (c) as a coating applied to all or parts of both surfaces; and/or(d) incorporated into the polymers which comprise the urethral stent.

Drug-coating of, or drug incorporation into, the urethral stent willallow bacteriocidal drug levels to be achieved locally on the stentsurface, thus reducing the incidence of bacterial colonization (andsubsequent development of pyelonephritis and/or bacteremia), whileproducing negligible systemic exposure to the drugs. Although for someagents polymeric carriers are not required for attachment of the drug tothe ureteral stent surface, several polymeric carriers are particularlysuitable for use in this embodiment. Of particular interest arepolymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A [CTBiomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As urethral stents are prone to the same complications and infectionsfrom the same bacteria, the dosing guidelines for doxorubicin,mitoxantrone, 5-fluorouracil and etoposide in coating ureteral stentsare identical to those described above for urinary catheters. However,unlike the formulations described for urinary catheters, drug releaseshould occur over a 2 to 24 week period.

Prosthetic Bladder Sphincters

Prosthetic bladder sphincters are used to treat incontinence andgenerally consist of a periurethral implant. The placement of prostheticbladder sphincters can be complicated by infection (usually in the first6 months after surgery) with Coagulase Negative Staphylococci (includingStaphylococcus epidermidis), Staphylococcus aureus, Pseudomonasaeruginosa, Enterococci, Serratia and Candida. Infection ischaracterized by fever, erythema, induration and purulent drainage fromthe operative site. The usual route of infection is through the incisionat the time of surgery and up to 3% of prosthetic bladder sphinctersbecome infected despite the best sterile surgical technique. To helpcombat this, intraoperative irrigation with antibiotic solutions isoften employed.

Treatment of infections of prosthetic bladder sphincters requirescomplete removal of the device and antibiotic therapy; replacement ofthe device must often be delayed for 3-6 months after the infection hascleared. An effective prosthetic bladder sphincter coating would resistinfection and reduce the incidence of re-intervention.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe prosthetic bladder sphincter. The drug(s) can be applied in severalmanners: (a) as a coating applied to the external surface of theprosthetic bladder sphincter; and/or (b) incorporated into the polymerswhich comprise the prosthetic bladder sphincter.

Drug-coating of, or drug incorporation into, the prosthetic bladdersphincter will allow bacteriocidal drug levels to be achieved locally,thus reducing the incidence of bacterial colonization (and subsequentdevelopment of urethritis and/or wound infection), while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug to theprosthetic bladder sphincter surface, several polymeric carriers areparticularly suitable for use in this embodiment. Of particular interestare polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A[CT Biomaterials], HydroMed640™ [CT Biomaterials], HYDROSLIP C™ [CTBiomaterials], HYDROTHANE™ [CT Biomaterials]), acrylic or methacryliccopolymers (e.g. poly(ethylene-co-acrylic acid), cellulose-derivedpolymers (e.g. nitrocellulose, Cellulose Acetate Butyrate, Celluloseacetate propionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As prosthetic bladder sphincters are prone to infections caused by thesame bacteria as occur with urinary catheters, the dosing guidelines fordoxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coatingprosthetic bladder sphincters are identical to those described above forurinary catheters. However, unlike the formulations described forurinary catheters, drug release should occur over a 2 to 24 week period.

Penile Implants

Penile implants are used to treat erectile dysfunction and are generallyflexible rods, hinged rods or inflatable devices with a pump. Theplacement of penile implants can be complicated by infection (usually inthe first 6 months after surgery) with Coagulase Negative Staphylococci(including Staphylococcus epidermidis), Staphylococcus aureus,Pseudomonas aeruginosa, Enterococci, Serratia and Candida. The type ofdevice or route of insertion does not affect the incidence of infection.Infection is characterized by fever, erythema, induration and purulentdrainage from the operative site. The usual route of infection isthrough the incision at the time of surgery and up to 3% of penileimplants become infected despite the best sterile surgical technique. Tohelp combat this, intraoperative irrigation with antibiotic solutions isoften employed.

Treatment of infections of penile implants requires complete removal ofthe device and antibiotic therapy; replacement of the device must oftenbe delayed for 3-6 months after the infection has cleared. An effectivepenile implant coating would resist infection and reduce the incidenceof re-intervention.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe penile implant. The drug(s) can be applied in several manners: (a)as a coating applied to the external surface of the penile implant;and/or (b) incorporated into the polymers which comprise the penileimplant.

Drug-coating of, or drug incorporation into, the penile implant willallow bacteriocidal drug levels to be achieved locally, thus reducingthe incidence of bacterial colonization (and subsequent development oflocal infection and device failure), while producing negligible systemicexposure to the drugs. Although for some agents polymeric carriers arenot required for attachment of the drug to the penile implant surface,several polymeric carriers are particularly suitable for use in thisembodiment.

As penile implants are prone to infections caused by the same bacteriaas occur with urinary catheters, the dosing guidelines for doxorubicin,mitoxantrone, 5-fluorouracil and etoposide in coating penile implantsare identical to those described above for urinary catheters. However,unlike the formulations described for urinary catheters, drug releaseshould occur over a 2 to 24 week period.

H. Infections Associated with Endotracheal and Tracheostomy Tubes

Endotracheal tubes and tracheostomy tubes are used to maintain theairway when ventilatory assistance is required. Endotracheal tubes tendto be used to establish an airway in the acute setting, whiletracheostomy tubes are used when prolonged ventilation is required orwhen there is a fixed obstruction in the upper airway. In hospitalizedpatients, nosocomial pneumonia occurs 300,000 times per year and is thesecond most common cause of hospital-acquired infection (after urinarytract infection) and the most common infection in ICU patients. In theintensive care unit, nosocomial pneumonia is a frequent cause death withfatality rates over 50%. Survivors spend on average 2 weeks longer inhospital and the annual cost of treatment is close to $2 billion.

Bacterial pneumonia is the most common cause of excess morbidity andmortality in patients who require intubation. In patients who areintubated electively (i.e. for elective surgery), less than 1% willdevelop a nosocomial pneumonia. However, patients who are severely illwith ARDS (Adult Respiratory Distress Syndrome) have a greater than 50%chance of developing a nosocomial pneumonia. It is thought that neworganisms colonize the oropharynx in intubated patients, are swallowedto contaminate the stomach, are aspirated to inoculate the lower airwayand eventually contaminate the endotracheal tube. Bacteria adhere to thetube, form a biolayer and multiply serving as a source for bacteria thatcan aerosolize and be carried distally into the lungs. Chronictracheostomy tubes also frequently become colonized with pathogenicbacteria known to cause pneumonia. The most common causes of pneumoniain ventilated patients are Staphylococcus aureus (17%), Pseudomonasaeruginosa (18%), Klebsiella pneumoniae (9%), Enterobacter (9%) andHaemophilus influenza (5%). Treatment requires aggressive therapy withantibiotics.

An effective endotracheal tube or tracheostomy tube coating would resistinfection and prevent the formation of biofilm in the tube. An effectivecoating would prevent or reduce the incidence of pneumonia, sepsis anddeath. In a preferred embodiment, doxorubicin, mitoxantrone,5-fluorouracil and/or etoposide are formulated into a coating applied tothe surface of the endotracheal tube or tracheostomy tube. Due to itsactivity against Klebsiella pneumoniae, methotrexate can also be usefulfor this embodiment. As cisplatin and hydroxyurea have some activityagainst Pseudomonas aeruginosa, they can also be of some utility in thepractice of this embodiment. The drug(s) can be applied in severalmanners: (a) as a coating applied to the external surface of theendotracheal tube or tracheostomy tube; (b) as a coating applied to theinternal (luminal) surface of the endotracheal tube or tracheostomytube; (c) as a coating applied to all or parts of both surfaces; and/or(d) incorporated into the polymers which comprise the endotracheal tubeor tracheostomy tube.

Drug-coating of, or drug incorporation into, the endotracheal tube ortracheostomy tube will allow bacteriocidal drug levels to be achievedlocally on the catheter surface, thus reducing the incidence ofbacterial colonization (and subsequent development of pneumonia andsepsis), while producing negligible systemic exposure to the drugs.Although for some agents polymeric carriers are not required forattachment of the drug to the endotracheal tube or tracheostomy tubesurface, several polymeric carriers are particularly suitable for use inthis embodiment. Of particular interest are polymeric carriers such aspolyurethanes (e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™[CT Biomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As endotracheal tube and tracheostomy tubes are made in a variety ofconfigurations and sizes, the exact dose administered will vary withdevice size, surface area and design. However, certain principles can beapplied in the application of this art. Drug dose can be calculated as afunction of dose per unit area (of the portion of the device beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the endotracheal tube ortracheostomy tube, the preferred anticancer agents, used alone or incombination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the endotracheal tube or tracheostomy tubecomponents, or applied without a carrier polymer, the total dose ofdoxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg).In a particularly preferred embodiment, the total amount of drug appliedshould be in the range of 1 μg to 5 mg. The dose per unit area (i.e. theamount of drug as a function of the surface area of the portion of theendotracheal tube or tracheostomy tube to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-100 μg per mm² ofsurface area. In a particularly preferred embodiment, doxorubicin shouldbe applied to the endotracheal tube or tracheostomy tube surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release doxorubicin at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the endotracheal tube or tracheostomy tube surface suchthat a minimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintainedon the surface. It is necessary to insure that surface drugconcentrations exceed concentrations of doxorubicin known to be lethalto multiple species of bacteria and fungi (i.e., are in excess of 10⁻⁴M; although for some embodiments lower concentrations are sufficient).In a preferred embodiment, doxorubicin is released from the surface ofthe endotracheal tube or tracheostomy tube such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations from the endotracheal tube for aperiod ranging from 1 hour to 1 month, while release from a tracheostomytube would range from 1 day to 3 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the endotracheal tube or tracheostomy tube, or applied without acarrier polymer, the total dose of mitoxantrone applied should notexceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the endotracheal tube ortracheostomy tube to which drug is applied and/or incorporated) shouldfall within the range of 0.01 μg-20 μg per mm² of surface area. In aparticularly preferred embodiment, mitoxantrone should be applied to theendotracheal tube or tracheostomy tube surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe endotracheal tube or tracheostomy tube surface such that a minimumconcentration of 10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It isnecessary to insure that drug concentrations on the surface exceedconcentrations of mitoxantrone known to be lethal to multiple species ofbacteria and fungi (i.e. are in excess of 10⁻⁵ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, mitoxantrone is released from the endotracheal tube ortracheostomy tube surface such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment, the drug is released in effectiveconcentrations from the endotracheal tube for a period ranging from 1hour to 1 month, while release from a tracheostomy tube would range from1 day to 3 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of mitoxantrone (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the endotracheal tube or tracheostomy tube, orapplied without a carrier polymer, the total dose of 5-fluorouracilapplied should not exceed 250 mg (range of 1.0 μg to 250 mg). In aparticularly preferred embodiment, the total amount of drug appliedshould be in the range of 10 μg to 25 mg. The dose per unit area (i.e.the amount of drug as a function of the surface area of the portion ofthe endotracheal tube or tracheostomy tube to which drug is appliedand/or incorporated) should fall within the range of 0.1 μg-1 mg per mm²of surface area. In a particularly preferred embodiment, 5-fluorouracilshould be applied to the endotracheal tube or tracheostomy tube surfaceat a dose of 1.0 μg/mm²-50 μg/mm². As different polymer and non-polymercoatings will release 5-fluorouracil at differing rates, the abovedosing parameters should be utilized in combination with the releaserate of the drug from the endotracheal tube or tracheostomy tube surfacesuch that a minimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil ismaintained. It is necessary to insure that surface drug concentrationsexceed concentrations of 5-fluorouracil known to be lethal to numerousspecies of bacteria and fungi (i.e. are in excess of 10⁻⁴ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, 5-fluorouracil is released from the endotrachealtube or tracheostomy tube surface such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment, the drug is released in effectiveconcentrations from the endotracheal tube for a period ranging from 1hour to 1 month, while release from a tracheostomy tube would range from1 day to 3 months. It should be readily evident given the discussionsprovided herein that analogues and derivatives of 5-fluorouracil (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent as5-fluorouracil is administered at half the above parameters, a compoundhalf as potent as 5-fluorouracil is administered at twice the aboveparameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the endotracheal tube or tracheostomy tube, orapplied without a carrier polymer, the total dose of etoposide appliedshould not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularlypreferred embodiment, the total amount of drug applied should be in therange of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drugas a function of the surface area of the portion of the endotrachealtube or tracheostomy tube to which drug is applied and/or incorporated)should fall within the range of 0.01 μg-100 μg per mm² of surface area.In a particularly preferred embodiment, etoposide should be applied tothe endotracheal tube or tracheostomy tube surface at a dose of 0.1μg/mm²-10 μg/mm². As different polymer and non-polymer coatings willrelease etoposide at differing rates, the above dosing parameters shouldbe utilized in combination with the release rate of the drug from theendotracheal tube or tracheostomy tube surface such that a concentrationof 10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insurethat surface drug concentrations exceed concentrations of etoposideknown to be lethal to a variety of bacteria and fungi (i.e. are inexcess of 10⁻⁵ M; although for some embodiments lower drug levels willbe sufficient). In a preferred embodiment, etoposide is released fromthe surface of the endotracheal tube or tracheostomy tube such thatanti-infective activity is maintained for a period ranging from severalhours to several months. In a particularly preferred, embodiment thedrug is released in effective concentrations from the endotracheal tubefor a period ranging from 1 hour to 1 month, while release from atracheostomy tube would range from 1 day to 3 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theendotracheal tube or tracheostomy tube coating. Similarly anthracyclines(e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/orpodophylotoxins (e.g., etoposide) can be combined with traditionalantibiotic and/or antifungal agents to enhance efficacy.

I. Infections Associated with Dialysis Catheters

In 1997, there were over 300,000 patients in the United States withend-stage renal disease. Of these, 63% were treated with hemodialysis,9% with peritoneal dialysis and 38% with renal transplantation.Hemodialysis requires reliable access to the vascular system typicallyas a surgically created arteriovenous fistula (AVF; 18%), via asynthetic bridge graft (usually a PTFE arteriovenous interposition graftin the forearm or leg; 50%) or a central venous catheter (32%).Peritoneal dialysis requires regular exchange of dialysate through theperitoneum via a double-cuffed and tunnelled peritoneal dialysiscatheter. Regardless of the form of dialysis employed, infection is thesecond leading cause of death in renal failure patients (15.5% of alldeaths) after heart disease. A significant number of those infectionsare secondary to the dialysis procedure itself.

Hemodialysis Access Grafts

Kidney failure patients have a dysfunctional immune response that makesthem particularly susceptible to infection. Infections of hemodialysisaccess grafts are characterized as either being early (within month;thought to be a complication of surgery) and late (after 1 month;thought to be related to access care). Over a 2 year period,approximately 2% of AVF's become infected while 11-16% of PTFE graftswill become infected on at least one occasion. Although infection canresult from extension of an infection from an adjacent contaminatedtissue or hematogenous seeding, the most common cause of infection isintraoperative contamination. The most common causes of infectioninclude Staphylococcus aureus, Enterobacteriaceae, Pseudomonasaerugenosa, and Coagulase Negative Staphylococci.

Complications arising from hemodialysis access graft infection includesepsis, subcutaneous infection, false aneurysm formation, endocarditis,osteomyelitis, septic arthritis, haemorrhage, septic or thromboticemboli, graft thrombosis and septic death (2-4% of all infections).Treatment often requires removal of part or all of the graft combinedwith systemic antibiotics.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe components of the synthetic hemodialysis access graft. The drug(s)can be applied in several manners: (a) as a coating applied to theexternal surface of the graft; (b) as a coating applied to the internal(luminal) surface of the graft; and/or (c) as a coating applied to allor parts of both surfaces. For an AVF, the drug would be formulated intoa surgical implant placed around the outside of the fistula at the timeof surgery.

Drug-coating of, or drug incorporation into hemodialysis access graftswill allow bacteriocidal drug levels to be achieved locally on the graftsurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug, severalpolymeric carriers are particularly suitable for use in this embodiment.Of particular interest are polymeric carriers such as polyurethanes(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CTBiomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)), collagen, PLG as well as blendsthereof.

An effective hemodialysis access graft coating would reduce theincidence of complications such as sepsis, haemorrhage, thrombosis,embolism, endocarditis, osteomyelitis and even death. An effectivecoating would also decrease the number of hemodialysis access graftsrequiring replacement, resulting in lower mortality and morbidity forpatients with these implants.

As hemodialysis access grafts are made in a variety of configurationsand sizes, the exact dose administered will vary with device size,surface area, design and portions of the graft coated. However, certainprinciples can be applied in the application of this art. Drug dose canbe calculated as a function of dose per unit area (of the portion of thedevice being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the hemodialysisaccess graft, the preferred anticancer agents, used alone or incombination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the hemodialysis access graft components (such asDacron or Teflon), or applied without a carrier polymer, the total doseof doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 1 μg to 5 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the hemodialysis access graft to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-100 μg per mm² ofsurface area. In a particularly preferred embodiment, doxorubicin shouldbe applied to the hemodialysis access graft surface at a dose of 0.1μg/mm²-10 μg/mm². As different polymer and non-polymer coatings willrelease doxorubicin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe hemodialysis access graft surface such that a minimum concentrationof 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on the surface. It isnecessary to insure that surface drug concentrations exceedconcentrations of doxorubicin known to be lethal to multiple species ofbacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower concentrations are sufficient). In a preferredembodiment, doxorubicin is released from the surface of the hemodialysisaccess graft such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the hemodialysis access graft (such as Dacron or Teflon), or appliedwithout a carrier polymer, the total dose of mitoxantrone applied shouldnot exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the hemodialysis accessgraft to which drug is applied and/or incorporated) should fall withinthe range of 0.01 μg-20 μg per mm² of surface area. In a particularlypreferred embodiment, mitoxantrone should be applied to the hemodialysisaccess graft surface at a dose of 0.05 μg/mm²-3 μg/mm². As differentpolymer and non-polymer coatings will release mitoxantrone at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the hemodialysis access graftsurface such that a minimum concentration of 10⁻⁵-10⁻⁶ M of mitoxantroneis maintained. It is necessary to insure that drug concentrations on thesurface exceed concentrations of mitoxantrone known to be lethal tomultiple species of bacteria and fungi (i.e. are in excess of 10⁻⁵ M;although for some embodiments lower drug levels will be sufficient). Ina preferred embodiment, mitoxantrone is released from the hemodialysisaccess graft surface such that anti-infective activity is maintained fora period ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofmitoxantrone (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as mitoxantrone is administered at half theabove parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the hemodialysis access graft (such as Dacron orTeflon), or applied without a carrier polymer, the total dose of5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 10 μg to 25 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the hemodialysis access graft to which drug is applied and/orincorporated) should fall within the range of 0.1 μg-1 mg per mm² ofsurface area. In a particularly preferred embodiment, 5-fluorouracilshould be applied to the hemodialysis access graft surface at a dose of1.0 μg/mm²-50 μg/mm². As different polymer and non-polymer coatings willrelease 5-fluorouracil at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe hemodialysis access graft surface such that a minimum concentrationof 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. It is necessary toinsure that surface drug concentrations exceed concentrations of5-fluorouracil known to be lethal to numerous species of bacteria andfungi (i.e., are in excess of 10⁻⁴ M; although for some embodimentslower drug levels will be sufficient). In a preferred embodiment,5-fluorouracil is released from the hemodialysis access graft surfacesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1 week-6 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the hemodialysis access graft (such as Dacron orTeflon), or applied without a carrier polymer, the total dose ofetoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). Ina particularly preferred embodiment, the total amount of drug appliedshould be in the range of 1 μg to 5 mg. The dose per unit area (i.e. theamount of drug as a function of the surface area of the portion of thehemodialysis access graft to which drug is applied and/or incorporated)should fall within the range of 0.01 μg-100 μg per mm² of surface area.In a particularly preferred embodiment, etoposide should be applied tothe hemodialysis access graft surface at a dose of 0.1 μg/mm²-10 μg/mm².As different polymer and non-polymer coatings will release etoposide atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the hemodialysisaccess graft surface such that a concentration of 10⁻⁵-10⁻⁶ M ofetoposide is maintained. It is necessary to insure that surface drugconcentrations exceed concentrations of etoposide known to be lethal toa variety of bacteria and fungi (i.e. are in excess of 10⁻⁵ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, etoposide is released from the surface of thehemodialysis access graft such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of thehemodialysis access graft coating. Similarly anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and/or podophylotoxins(e.g., etoposide) can be combined with traditional antibiotic and/orantifungal agents to enhance efficacy. Since thrombogenicity of thehemodialysis access graft is associated with an increased risk ofinfection, anthracyclines (e.g., doxorubicin or mitoxantrone),fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g.,methotrexate) and/or podophylotoxins (e.g., etoposide) can be combinedwith antithrombotic and/or antiplatelet agents (for example heparin,dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate,hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel,abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissueplasminogen activator) to enhance efficacy.

Central Venous Catheters

A variety of central venous catheters are available for use inhemodialysis including, but not restricted to, catheters which aretotally implanted such as the Lifesite (Vasca Inc., Tewksbury, Mass.)and the Dialock (Biolink Corp., Middleboro, Mass.). Central venouscatheters are prone to infection and embodiments for that purpose aredescribed above.

Peritoneal Dialysis Catheters

Peritoneal dialysis catheters are typically double-cuffed and tunnelledcatheters that provide access to the peritoneum. The most commonperitoneal dialysis catheter designs are the Tenckhoff catheter, theSwan Neck Missouri catheter and the Toronto Western catheter. Inperitoneal dialysis, the peritoneum acts as a semipermeable membraneacross which solutes can be exchanged down a concentration gradient.

Peritoneal dialysis infections are typically classified as eitherperitonitis or exit-site/tunnel infections (i.e. catheter infections).Exit-site/tunnel infections are characterized by redness, induration orpurulent discharge from the exit site or subcutaneous portions of thecatheter. Peritonitis is more a severe infection that causes abdominalpain, nausea, fever and systemic evidence of infection. Unfortunately,the peritoneal dialysis catheter likely plays a role in both types ofinfection. In exit-site/tunnel infections, the catheter itself becomesinfected. In peritonitis, the infection is frequently the result ofbacteria tracking from the skin through the catheter lumen or migratingon the outer surface (pericatheter route) of the catheter into theperitoneum. Peritoneal catheter-related infections are typically causedby Staphylococcus aureus, Coagulase Negative Staphylococci, Escherichiacoli, Viridans group streptococci, Enterobacteriacae, Corynebacterium,Branhamella, Actinobacter, Serratia, Proteus, Pseudomonas aeruginosa andFungi.

Treatment of peritonitis involves rapid in-and-out exchanges ofdialysate, systemic antibiotics (intravenous and/or intraperitonealadministration) and often requires removal of the catheter.Complications include hospitalization, the need to switch to anotherform of dialysis (30%) and mortality (2%; higher if the infection is dueto Enterococci, S. aureus or polymicrobial).

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe components of the synthetic peritoneal dialysis graft. The drug(s)can be applied in several manners: (a) as a coating applied to theexternal surface of the graft; (b) as a coating applied to the internal(luminal) surface of the graft; (c) as a coating applied to thesuperficial cuff; (d) as a coating applied to the deep cuff; (e)incorporated into the polymers that comprise the graft; and/or (f) as acoating applied to a combination of these surfaces.

Drug-coating of, or drug incorporation into peritoneal dialysis graftswill allow bacteriocidal drug levels to be achieved locally on the graftsurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug, severalpolymeric carriers are particularly suitable for use in this embodiment.Of particular interest are polymeric carriers such as polyurethanes(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CTBiomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

An effective peritoneal dialysis graft coating would reduce theincidence of complications such as hospitalization, peritonoitis,sepsis, and even death. An effective coating would also decrease thenumber of peritoneal dialysis grafts requiring replacement, resulting inlower mortality and morbidity for patients with these implants.

As peritoneal dialysis grafts are made in a variety of configurationsand sizes, the exact dose administered will vary with device size,surface area, design and portions of the graft coated. However, certainprinciples can be applied in the application of this art. Drug dose canbe calculated as a function of dose per unit area (of the portion of thedevice being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the peritonealdialysis graft, the preferred anticancer agents, used alone or incombination, should be administered under the following dosingguidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the peritoneal dialysis graft components (such asDacron or Teflon), or applied without a carrier polymer, the total doseof doxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 1 μg to 5 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the peritoneal dialysis graft to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-100 μg per mm² ofsurface area. In a particularly preferred embodiment, doxorubicin shouldbe applied to the peritoneal dialysis graft surface at a dose of 0.1μg/mm²-10 μg/mm². As different polymer and non-polymer coatings willrelease doxorubicin at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe peritoneal dialysis graft surface such that a minimum concentrationof 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on the surface. It isnecessary to insure that surface drug concentrations exceedconcentrations of doxorubicin known to be lethal to multiple species ofbacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower concentrations are sufficient). In a preferredembodiment, doxorubicin is released from the surface of the peritonealdialysis graft such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1 week-6 months. It should be readily evidentgiven the discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the peritoneal dialysis graft (such as Dacron or Teflon), or appliedwithout a carrier polymer, the total dose of mitoxantrone applied shouldnot exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the peritoneal dialysisgraft to which drug is applied and/or incorporated) should fall withinthe range of 0.01 μg-20 μg per mm² of surface area. In a particularlypreferred embodiment, mitoxantrone should be applied to the peritonealdialysis graft surface at a dose of 0.05 μg/mm²-3 μg/mm². As differentpolymer and non-polymer coatings will release mitoxantrone at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the peritoneal dialysis graftsurface such that a minimum concentration of 10⁵-10⁻⁶ M of mitoxantroneis maintained. It is necessary to insure that drug concentrations on thesurface exceed concentrations of mitoxantrone known to be lethal tomultiple species of bacteria and fungi (i.e. are in excess of 10⁻⁵ M;although for some embodiments lower drug levels will be sufficient). Ina preferred embodiment, mitoxantrone is released from the peritonealdialysis graft surface such that anti-infective activity is maintainedfor a period ranging from several hours to several months. In aparticularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of mitoxantrone (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as mitoxantrone is administered at halfthe above parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the peritoneal dialysis graft (such as Dacron orTeflon), or applied without a carrier polymer, the total dose of5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 10 μg to 25 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the peritoneal dialysis graft to which drug is applied and/orincorporated) should fall within the range of 0.1 μg-1 mg per mm² ofsurface area. In a particularly preferred embodiment, 5-fluorouracilshould be applied to the peritoneal dialysis graft surface at a dose of1.0 μg/mm²-50 μg/mm². As different polymer and non-polymer coatings willrelease 5-fluorouracil at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe peritoneal dialysis graft surface such that a minimum concentrationof 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. It is necessary toinsure that surface drug concentrations exceed concentrations of5-fluorouracil known to be lethal to numerous species of bacteria andfungi (i.e., are in excess of 10⁻⁴ M; although for some embodimentslower drug levels will be sufficient). In a preferred embodiment,5-fluorouracil is released from the peritoneal dialysis graft surfacesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1 week-6 months. It should be readily evident given thediscussions provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the peritoneal dialysis graft (such as Dacron orTeflon), or applied without a carrier polymer, the total dose ofetoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). Ina particularly preferred embodiment, the total amount of drug appliedshould be in the range of 1 μg to 5 mg. The dose per unit area (i.e. theamount of drug as a function of the surface area of the portion of theperitoneal dialysis graft to which drug is applied and/or incorporated)should fall within the range of 0.01 μg-100 μg per mm² of surface area.In a particularly preferred embodiment, etoposide should be applied tothe peritoneal dialysis graft surface at a dose of 0.1 μg/mm²-10 μg/mm².As different polymer and non-polymer coatings will release etoposide atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the peritonealdialysis graft surface such that a concentration of 10⁻⁵-10⁻⁶ M ofetoposide is maintained. It is necessary to insure that surface drugconcentrations exceed concentrations of etoposide known to be lethal toa variety of bacteria and fungi (i.e. are in excess of 10⁻⁵ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, etoposide is released from the surface of theperitoneal dialysis graft such that anti-infective activity ismaintained for a period ranging from several hours to several months. Ina particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1 week-6 months. It should bereadily evident given the discussions provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theperitoneal dialysis graft coating. Similarly anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and/or podophylotoxins(e.g., etoposide) can be combined with traditional antibiotic and/orantifungal agents to enhance efficacy.

J. Infections of Central Nervous System (CNS) Shunts

Hydrocephalus, or accumulation of cerebrospinal fluid (CSF) in thebrain, is a frequently encountered neurosurgical condition arising fromcongenital malformations, infection, hemmorrhage, or malignancy. Theincompressible fluid exerts pressure on the brain leading to braindamage or even death if untreated. CNS shunts are conduits placed in theventricles of the brain to divert the flow of CSF from the brain toother body compartments and relieve the fluid pressure. Ventricular CSFis diverted via a prosthetic shunt to a number of drainage locationsincluding the pleura (ventriculopleural shunt), jugular vein, vena cava(VA shunt), gallbladder and peritoneum (VP shunt; most common).

Unfortunately, CSF shunts are relatively prone to developing infection,although the incidence has declined from 25% twenty years ago to 10% atpresent as a result of improved surgical technique. Approximately 25% ofall shunt complications are due to the development of infection of theshunt and these can lead to significant clinical problems such asventriculitis, ventricular compartmentalization, meningitis, subduralempyema, nephritis (with VA shunts), seizures, cortical mantle thinning,mental retardation or death. Most infections present with fever, nausea,vomiting, malaise, or signs of increased intracranial pressure such asheadache or altered consciousness. The most common organisms causing CNSshunt infections are Coagulase Negative Staphylococci (67%;Staphylococcus epidermidis is the most frequently isolated organism),Staphylococcus aureus (10-20%), viridans streptococci, Streptococcuspyogenes, Enterococcus, Corynebacterium, Escherichia coli, Klebsiella,Proteus and Pseudomonas aeruginosa. It is thought that the majority ofinfections are due to inoculation of the organism during surgery, orduring manipulation of the shunt in the postoperative period. As aresult, most infections present clinically in the first few weeksfollowing surgery.

Since many of the infections are caused by S. epidermidis, it is notuncommon to find that the catheter becomes coated with abacterial-produced “slime” that protects the organism from the immunesystem and makes eradication of the infection difficult. Therefore, thetreatments of most infections require shunt removal (and often placementof a temporary external ventricular shunt to relieve hydrocephalus) inaddition to systemic and/or intraventricular antibiotic therapy. Poortherapeutic results tend to occur if the shunt is left in place duringtreatment. Antibiotic therapy is complicated by the fact that manyantibiotics do not cross the blood-brain barrier effectively.

An effective CNS shunt coating would reduce the incidence ofcomplications such as ventriculitis, ventricular compartmentalization,meningitis, subdural empyema, nephritis (with VA shunts), seizures,cortical mantle thinning, mental retardation or death. An effectivecoating would also decrease the number of CNS shunts requiringreplacement, resulting in lower mortality and morbidity for patientswith these implants.

In a preferred embodiment, an anthracycline (e.g., doxorubicin andmitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist(e.g., methotrexate), and/or podophylotoxin (e.g., etoposide) isformulated into a coating applied to the surface of the components ofthe CNS shunt. The drug(s) can be applied in several manners: (a) as acoating applied to the external surface of the shunt; (b) as a coatingapplied to the internal (luminal) surface of the shunt; and/or (c) as acoating applied to all or parts of both surfaces.

Drug-coating of, or drug incorporation into CNS shunts will allowbacteriocidal drug levels to be achieved locally on the shunt surface,thus reducing the incidence of bacterial colonization and subsequentdevelopment of infectious complications, while producing negligiblesystemic exposure to the drugs. Although for some agents polymericcarriers are not required for attachment of the drug, several polymericcarriers are particularly suitable for use in this embodiment. Ofparticular interest are polymeric carriers such as polyurethanes (e.g.,ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CT Biomaterials],HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CT Biomaterials]), acrylicor methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid),cellulose-derived polymers (e.g. nitrocellulose, Cellulose AcetateButyrate, Cellulose acetate propionate), acrylate and methacrylatecopolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blendsthereof.

As CNS shunts are made in a variety of configurations and sizes, theexact dose administered will vary with device size, surface area, designand portions of the shunt coated. However, certain principles can beapplied in the application of this art. Drug dose can be calculated as afunction of dose per unit area (of the portion of the device beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the CNS shunt, the preferredanticancer agents, used alone or in combination, should be administeredunder the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the CNS shunt components (such as Dacron orTeflon), or applied without a carrier polymer, the total dose ofdoxorubicin applied should not exceed 25 mg (range of 0.1 μg to 25 mg).In a particularly preferred embodiment, the total amount of drug appliedshould be in the range of 1 μg to 5 mg. The dose per unit area (i.e. theamount of drug as a function of the surface area of the portion of theCNS shunt to which drug is applied and/or incorporated) should fallwithin the range of 0.01 μg-100 μg per mm² of surface area. In aparticularly preferred embodiment, doxorubicin should be applied to theCNS shunt surface at a dose of 0.1 μg/mm²-10 μg/mm². As differentpolymer and non-polymer coatings will release doxorubicin at differingrates, the above dosing parameters should be utilized in combinationwith the release rate of the drug from the CNS shunt surface such that aminimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on thesurface. It is necessary to insure that surface drug concentrationsexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of theCNS shunt such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-12 weeks. It should be readily evident giventhe discussions provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the CNS shunt (such as Dacron or Teflon), or applied without acarrier polymer, the total dose of mitoxantrone applied should notexceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of0.1 μg to 1 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the CNS shunt to whichdrug is applied and/or incorporated) should fall within the range of0.01 μg-20 μg per mm² of surface area. In a particularly preferredembodiment, mitoxantrone should be applied to the CNS shunt surface at adose of 0.05 μg/mm²-3 μg/mm². As different polymer and non-polymercoatings will release mitoxantrone at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the CNS shunt surface such that a minimum concentration of10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It is necessary to insurethat drug concentrations on the surface exceed concentrations ofmitoxantrone known to be lethal to multiple species of bacteria andfungi (i.e. are in excess of 10⁻⁵ M; although for some embodiments lowerdrug levels will be sufficient). In a preferred embodiment, mitoxantroneis released from the CNS shunt surface such that anti-infective activityis maintained for a period ranging from several hours to several months.In a particularly preferred embodiment the drug is released in effectiveconcentrations for a period ranging from 1-12 weeks. It should bereadily evident based upon the discussion provided herein that analoguesand derivatives of mitoxantrone (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as mitoxantrone is administered at halfthe above parameters, a compound half as potent as mitoxantrone isadministered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the CNS shunt (such as Dacron or Teflon), orapplied without a carrier polymer, the total dose of 5-fluorouracilapplied should not exceed 250 mg (range of 1.0 μg to 250 mg). In aparticularly preferred embodiment, the total amount of drug appliedshould be in the range of 10 μg to 25 mg. The dose per unit area (i.e.the amount of drug as a function of the surface area of the portion ofthe CNS shunt to which drug is applied and/or incorporated) should fallwithin the range of 0.1 μg-1 mg per mm² of surface area. In aparticularly preferred embodiment, 5-fluorouracil should be applied tothe CNS shunt surface at a dose of 1.0 μg/mm²-50 μg/mm². As differentpolymer and non-polymer coatings will release 5-fluorouracil atdiffering rates, the above dosing parameters should be utilized incombination with the release rate of the drug from the CNS shunt surfacesuch that a minimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil ismaintained. It is necessary to insure that surface drug concentrationsexceed concentrations of 5-fluorouracil known to be lethal to numerousspecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower drug levels will be sufficient). In apreferred embodiment, 5-fluorouracil is released from the CNS shuntsurface such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-12 weeks. It should be readily evident basedupon the discussion provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the CNS shunt (such as Dacron or Teflon), orapplied without a carrier polymer, the total dose of etoposide appliedshould not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularlypreferred embodiment, the total amount of drug applied should be in therange of 1 μg to 5 mg. The dose per unit area (i.e. the amount of drugas a function of the surface area of the portion of the CNS shunt towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the CNS shunt surface at adose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release etoposide at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the CNS shunt surface such that a concentration of10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insure thatsurface drug concentrations exceed concentrations of etoposide known tobe lethal to a variety of bacteria and fungi (i.e. are in excess of 10⁻⁵M; although for some embodiments lower drug levels will be sufficient).In a preferred embodiment, etoposide is released from the surface of theCNS shunt such that anti-infective activity is maintained for a periodranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-12 weeks. It should be readily evident basedupon the discussion provided herein that analogues and derivatives ofetoposide (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as etoposide is administered at half the aboveparameters, a compound half as potent as etoposide is administered attwice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theCNS shunt coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy.

(g) External Ventricular Drainage (EVD) Device and Intracranial Pressure(ICP) Monitoring Devices

EVD and ICP monitoring devices are also used in the management ofhydrocephalus. The therapeutic agents, doses, coatings and releasekinetics for the development of drug-coated EVD's and drug-coated ICPmonitoring devices are identical to those described for CNS shunts.

K. Infections of Orthopedic Implants

Implanted orthopedic devices such as prosthetic joints such as hip,knee, elbow, shoulder, wrist, metacarpal, and metatarsal prosthetics aresubject to complications as a result of infection of the implant.Orthopedic implant infection has a variety of sequela including pain,immobility, failure of the prosthetic itself, loss/removal the ofprosthetic, reoperation, loss of the affected limb or even death. Thecost of treating each infection exceeds the cost of the primary jointarthroplasty itself by 3 or 4-fold (in excess of $50,000/case). Otherorthopedic implant hardware such as internal and external fixationdevices, plates and screws are also subject to such infection andinfection-related complications. The present treatment includes multipleoperations to remove infected prosthetics, with its own inherent risks,combined with antibiotic use.

The rate of orthopedic prosthetic infection is highest in the firstmonth post operatively then declines continuously there after. As anexample, the combined incidence of rate of prosthetic joint infectionfor 2 years is approximately 5.9% per 1,000 joints; the rate then dropsto 2.3% per 1,000 joints from year 2 to 10. The rate of infection alsovaries depending on the joint. Knee prosthetics are infected twice asfrequently as hips. Shoulder prosthetic infections range from 0.5% to3%, elbows up to 12%, wrists 1.5% to 5.0% and ankles 1.4% to 2.4%.

There are three main mechanisms of infection. The most common iscolonization of the implant (prosthetic, fixation plate, screws—anyimplantable orthopedic device) at the time of implant, either directlyor through airborne contamination of the wound. The second method isspread from an adjacent focus of infection, such as wound infection,abscess or sinus tract. The third is hematogenous seeding during asystemic bacteremia, likely accounting for approximately 7% of allimplant infections.

Risk factors are multiple. The host may be compromised as a result of asystemic condition, an illness, a local condition, or as a result ofmedications that decrease the host defence capability. There is also apredisposition to infections if the patient has had prior surgery,perioperative wound compilations, or rheumatoid arthritis. Repeatsurgical procedures increase the likelihood of infection as there is areported 8-fold elevated risk of infection as compared to the primaryprosthetic replacement procedure. The presence of a deep infectionincreases the risk of prosthetic infection 6-fold. Various diseases alsoincrease the risk of infection. For example, rheumatoid arthritispatients have a higher risk of infection possibly as a result ofmedications that compromising their immunocompetency, while psoriaticpatients have a higher rate possibly mediated by a compromised skinbarrier that allows entry of microbes.

The implant itself, and the cements that secure it in place, can cause alocal immunocompromised condition that is poorly understood. Differentimplant materials have their own inherent rate of infection. Forexample, a metal-to-metal hinged prosthetic knee has 20-times the riskof infection of a metal-to-plastic knee.

An implanted device is most susceptible to infection early on. Rabbitmodels have shown that only a few Staphylococcus aureus inoculated atthe time of implant are required to cause an infection, but bacteremic(hematogenous) seeding at 3 weeks postoperatively is substantially moredifficult and requires significantly more bacteria. This emphasizes theimportance of an antimicrobial strategy initiated early at the time ofimplantation.

Sixty five percent of all prosthetic joint infections are caused by grampositive cocci, (Staphylococcus aureus, Coagulase NegativeStaphylococci, Beta-Hemolytic Streptococcus, Viridans GroupStreptococci) and enterococci. Often multiple strains of staphylococcuscan be present in a single prosthetic infection. Other organisms includeaerobic gram negative bacilli, Enterobacteriacea, Pseudomonas aeruginosaand Anaerobes (such as Peptostreptococcus and Bacteroides species).Polymicrobial infections account for 12% of infections.

The diagnosis of an infected implant is difficult due to the highlyvariable presentation; fever, general malaise, swelling, erythema, jointpain, loosening of the implant, or even acute septicemia. Fulminatepresentations are typically caused by more virulent organisms such asStapylococcus arureus and pyogneic beta-hemolytic streptococci. Chronicindolent courses are more typical of coagulase-negative staphylococci.

Management of an infected orthopedic implant usually requires prolongeduse of antibiotics and surgery to remove the infected device. Surgeryrequires debridement of the infected tissue, soft tissue, bone, cement,and removal of the infected implant. After a period of prolongedantibiotic use (weeks, months and sometimes a year to ensure microbialeradication), it is possible to implant a replacement prosthesis. Someauthors advocate the use of antibiotic impregnated cement, but citeconcerns regarding the risk of developing antibiotic resistance;especially methecillin resistance. If bone loss is extensive, anarthrodesis is often performed and amputation is necessary in somecases. Even when an infection is eradicated, the patient can be leftseverely compromised physically, have significant pain and carry a highrisk of re-infection.

It is therefore extremely clinically important to develop orthopedicimplants capable of resisting or reducing the rate of infection. Aneffective orthopedic implant coating would reduce the incidence of jointand hardware infection; lower the incidence of prosthetic failure,sepsis, amputation and even death; and also decrease the number oforthopedic implants requiring replacement, resulting in lower morbidityfor patients with these implants.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe components of the orthopedic implant. The drug(s) can be applied inseveral manners: (a) as a coating applied to the external intraosseoussurface of the prosthesis; (b) as a coating applied to the external(articular) surface of the prosthesis; (c) as a coating applied to allor parts of both surfaces; (d) as a coating applied to the surface ofthe orthopedic hardware (plates, screws, etc); (e) incorporated into thepolymers which comprise the prosthetic joints (e.g. articular surfacesand other surface coatings) and hardware (e.g. polylactic acid screwsand plates); and/or (f) incorporated into the components of the cementsused to secure the orthopedic implants in place.

Drug-coating of, or drug incorporation into orthopedic implant willallow bacteriocidal drug levels to be achieved locally on the implantsurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug, severalpolymeric carriers are particularly suitable for use in this embodiment.Of particular interest are polymeric carriers such as polyurethanes(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CTBiomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

The drugs of interest can also be incorporated into calcium phosphate orhydroxyapatite coatings on the medical devices.

As orthopedic implants are made in a variety of configurations andsizes, the exact dose administered will vary with implant size, surfacearea, design and portions of the implant coated. However, certainprinciples can be applied in the application of this art. Drug dose canbe calculated as a function of dose per unit area (of the portion of theimplant being coated), total drug dose administered can be measured andappropriate surface concentrations of active drug can be determined.Regardless of the method of application of the drug to the orthopedicimplant, the preferred anticancer agents, used alone or in combination,should be administered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the orthopedic implant components, or appliedwithout a carrier polymer, the total dose of doxorubicin applied shouldnot exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the orthopedic implant towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the orthopedic implantsurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release doxorubicin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the orthopedic implant surface such that aminimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on thesurface. It is necessary to insure that surface drug concentrationsexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of theorthopedic implant such that anti-infective activity is maintained for aperiod ranging from several hours to several months. As describedpreviously, the risk of infectious contamination of the implant isgreatest over the first 3 days. Therefore, in a particularly preferredembodiment, the majority (or all) of the drug is released over the first72 hours to prevent infection while allowing normal healing to occurthereafter. It should be readily evident based upon the discussionprovided herein that analogues and derivatives of doxorubicin (asdescribed previously) with similar functional activity can be utilizedfor the purposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g., a compound twice as potent asdoxorubicin is administered at half the above parameters, a compoundhalf as potent as doxorubicin is administered at twice the aboveparameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the orthopedic implant, or applied without a carrier polymer, thetotal dose of mitoxantrone applied should not exceed 5 mg (range of 0.01μg to 5 mg). In a particularly preferred embodiment, the total amount ofdrug applied should be in the range of 0.1 μg to 1 mg. The dose per unitarea (i.e. the amount of drug as a function of the surface area of theportion of the orthopedic implant to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-20 μg per mm² ofsurface area. In a particularly preferred embodiment, mitoxantroneshould be applied to the orthopedic implant surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe orthopedic implant surface such that a minimum concentration of10⁵-10⁻⁶ M of mitoxantrone is maintained. It is necessary to insure thatdrug concentrations on the surface exceed concentrations of mitoxantroneknown to be lethal to multiple species of bacteria and fungi (i.e. arein excess of 10⁻⁵ M; although for some embodiments lower drug levelswill be sufficient). In a preferred embodiment, mitoxantrone is releasedfrom the orthopedic implant surface such that anti-infective activity ismaintained for a period ranging from several hours to several months. Asdescribed previously, the risk of infectious contamination of theimplant is greatest over the first 3 days. Therefore, in one embodiment,the majority (or all) of the drug is released over the first 72 hours toprevent infection while allowing normal healing to occur thereafter. Itshould be readily evident based upon the discussion provided herein thatanalogues and derivatives of mitoxantrone (as described previously) withsimilar functional activity can be utilized for the purposes of thisinvention; the above dosing parameters are then adjusted according tothe relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as mitoxantrone isadministered at half the above parameters, a compound half as potent asmitoxantrone is administered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the orthopedic implant, or applied without acarrier polymer, the total dose of 5-fluorouracil applied should notexceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the orthopedic implant towhich drug is applied and/or incorporated) should fall within the rangeof 0.1 μg-1 mg per mm² of surface area. In a particularly preferredembodiment, 5-fluorouracil should be applied to the orthopedic implantsurface at a dose of 1.0 μg/mm²-50 μg/mm². As different polymer andnon-polymer coatings will release 5-fluorouracil at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the orthopedic implant surface such that aminimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. Itis necessary to insure that surface drug concentrations exceedconcentrations of 5-fluorouracil known to be lethal to numerous speciesof bacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, 5-fluorouracil is released from the orthopedic implantsurface such that anti-infective activity is maintained for a periodranging from several hours to several months. As described previously,the risk of infectious contamination of the implant is greatest over thefirst 3 days. Therefore, in a particularly preferred embodiment, themajority (or all) of the drug is released over the first 72 hours toprevent infection while allowing normal healing to occur thereafter. Itshould be readily evident based upon the discussion provided herein thatanalogues and derivatives of 5-fluorouracil (as described previously)with similar functional activity can be utilized for the purposes ofthis invention; the above dosing parameters are then adjusted accordingto the relative potency of the analogue or derivative as compared to theparent compound (e.g. a compound twice as potent as 5-fluorouracil isadministered at half the above parameters, a compound half as potent as5-fluorouracil is administered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the orthopedic implant, or applied without acarrier polymer, the total dose of etoposide applied should not exceed25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the orthopedic implant towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the orthopedic implantsurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release etoposide at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the orthopedic implant surface such that aconcentration of 10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessaryto insure that surface drug concentrations exceed concentrations ofetoposide known to be lethal to a variety of bacteria and fungi (i.e.are in excess of 10⁻⁵ M; although for some embodiments lower drug levelswill be sufficient). In a preferred embodiment, etoposide is releasedfrom the surface of the orthopedic implant such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. As described previously, the risk of infectiouscontamination of the implant is greatest over the first 3 days.Therefore, in a particularly preferred embodiment, the majority (or all)of the drug is released over the first 72 hours to prevent infectionwhile allowing normal healing to occur thereafter. It should be readilyevident based upon the discussion provided herein that analogues andderivatives of etoposide (as described previously) with similarfunctional activity can be utilized for the purposes of this invention;the above dosing parameters are then adjusted according to the relativepotency of the analogue or derivative as compared to the parent compound(e.g. a compound twice as potent as etoposide is administered at halfthe above parameters, a compound half as potent as etoposide isadministered at twice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theorthopedic implant coating. Similarly anthracyclines (e.g., doxorubicinor mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy.

L. Infections Associated with Other Medical Devices and Implants

Implants are commonly used in the practice of medicine and surgery for awide variety of purposes. These include implants such as drainage tubes,biliary T-tubes, clips, sutures, meshes, barriers (for the prevention ofadhesions), anastomotic devices, conduits, irrigation fluids, packingagents, stents, staples, inferior vena cava filters, embolizationagents, pumps (for the delivery of therapeutics), hemostatic implants(sponges), tissue fillers, cosmetic implants (breast implants, facialimplants, prostheses), bone grafts, skin grafts, intrauterine devices(IUD), ligatures, titanium implants (particularly in dentistry), chesttubes, nasogastric tubes, percutaneous feeding tubes, colostomy devices,bone wax, and Penrose drains, hair plugs, ear rings, nose rings, andother piercing-associated implants, as well as anaesthetic solutions toname a few. Any foreign body when placed into the body is at risk fordeveloping an infection—particularly in the period immediately followingimplantation.

The drug-coating, dosing, surface concentrations and release kinetics ofthese implants is identical to the embodiment described above fororthopedic implants. In addition, doxorubicin, mitoxantrone,5-fluorouracil and/or etoposide can be added to solutions used inmedicine (storage solutions, irrigation fluids, saline, mannitol,glucose solutions, lipids, nutritional fluids, and anaestheticsolutions) to prevent infection transmitted via infectedsolutions/fluids used in patient management.

M. Infections Associated with Ocular Implants

The principle infections of medical device implants in the eye areendophthalmitis associated with intraocular lens implantation forcataract surgery and corneal infections secondary to contact lens use.

Infections of Intraocular Lenses

The number of intraocular lenses implanted in the United States hasgrown exponentially over the last decade. Currently, over 1 millionintraocular lenses are implanted annually, with the vast majority (90%)being placed in the posterior chamber of the eye. Endophthalmitis is themost common infectious complication of intraocular lens placement andoccurs in approximately 0.3% of surgeries (3,000 cases per year). Thevast majority are due to surgical contamination and have an onset within48 hours of the procedure.

The most common causes of endophthalmitis are Coagulase NegativeStaphylococci (principally Staphylococcus epidermidis), Staphylococcusaureus, Enterococci, and Proteus mirabilis. Symptoms of the conditioninclude blurred vision, ocular pain, headache, photophobia, and cornealedema. The treatment of endophthalmitis associated with cataract surgeryincludes vitrectomy and treatment with systemic and/or intravitrealantibiotic therapy. Although most cases do not require removal of thelens, in complicated cases, visual acuity can be permanently affectedand/or the lens must be removed and replaced at a later date. Aneffective intraocular lens coating would reduce the incidence ofendophthalmitis and also decrease the number of intraocular lensrequiring replacement, resulting in lower morbidity for patients withthese implants.

In a preferred embodiment, doxorubicin, mitoxantrone, 5-fluorouraciland/or etoposide are formulated into a coating applied to the surface ofthe components of the intraocular lens. The drug(s) can be applied inseveral manners: (a) as a coating applied to the external surface of thelens; (b) as a coating applied to the internal (luminal) surface of thelens; (c) as a coating applied to all or parts of both surfaces of thelens; and/or (d) incorporated into the polymers which comprise the lens.

Drug-coating of, or drug incorporation into intraocular lenses willallow bacteriocidal drug levels to be achieved locally on the lenssurface, thus reducing the incidence of bacterial colonization andsubsequent development of infectious complications, while producingnegligible systemic exposure to the drugs. Although for some agentspolymeric carriers are not required for attachment of the drug, severalpolymeric carriers are particularly suitable for use in this embodiment.Of particular interest are polymeric carriers such as polyurethanes(e.g., ChronoFlex AL 85A [CT Biomaterials], HydroMed640™ [CTBiomaterials], HYDROSLIP C™ [CT Biomaterials], HYDROTHANE™ [CTBiomaterials]), acrylic or methacrylic copolymers (e.g.poly(ethylene-co-acrylic acid), cellulose-derived polymers (e.g.nitrocellulose, Cellulose Acetate Butyrate, Cellulose acetatepropionate), acrylate and methacrylate copolymers (e.g.poly(ethylene-co-vinyl acetate)) as well as blends thereof.

As intraocular lenses are made in a variety of configurations and sizes,the exact dose administered will vary with lens size, surface area,design and portions of the lens coated. However, certain principles canbe applied in the application of this art. Drug dose can be calculatedas a function of dose per unit area (of the portion of the lens beingcoated), total drug dose administered can be measured and appropriatesurface concentrations of active drug can be determined. Regardless ofthe method of application of the drug to the intraocular lens, thepreferred anticancer agents, used alone or in combination, should beadministered under the following dosing guidelines:

(a) Anthracyclines. Utilizing the anthracycline doxorubicin as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the intraocular lens components, or appliedwithout a carrier polymer, the total dose of doxorubicin applied shouldnot exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the intraocular lens towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, doxorubicin should be applied to the intraocular lenssurface at a dose of 0.1 μg/mm²-10 μg/mm². As different polymer andnon-polymer coatings will release doxorubicin at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the intraocular lens surface such that aminimum concentration of 10⁻⁷-10⁻⁴ M of doxorubicin is maintained on thesurface. It is necessary to insure that surface drug concentrationsexceed concentrations of doxorubicin known to be lethal to multiplespecies of bacteria and fungi (i.e., are in excess of 10⁻⁴ M; althoughfor some embodiments lower concentrations are sufficient). In apreferred embodiment, doxorubicin is released from the surface of theintraocular lens such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-12 weeks. It should be readily evident basedupon the discussion provided herein that analogues and derivatives ofdoxorubicin (as described previously) with similar functional activitycan be utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as doxorubicin is administered at half theabove parameters, a compound half as potent as doxorubicin isadministered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whetherapplied as a polymer coating, incorporated into the polymers which makeup the intraocular lens, or applied without a carrier polymer, the totaldose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to5 mg). In a particularly preferred embodiment, the total amount of drugapplied should be in the range of 0.1 μg to 1 mg. The dose per unit area(i.e. the amount of drug as a function of the surface area of theportion of the intraocular lens to which drug is applied and/orincorporated) should fall within the range of 0.01 μg-20 μg per mm² ofsurface area. In a particularly preferred embodiment, mitoxantroneshould be applied to the intraocular lens surface at a dose of 0.05μg/mm²-3 μg/mm². As different polymer and non-polymer coatings willrelease mitoxantrone at differing rates, the above dosing parametersshould be utilized in combination with the release rate of the drug fromthe intraocular lens surface such that a minimum concentration of10⁻⁵-10⁻⁶ M of mitoxantrone is maintained. It is necessary to insurethat drug concentrations on the surface exceed concentrations ofmitoxantrone known to be lethal to multiple species of bacteria andfungi (i.e. are in excess of 10⁻⁵ M; although for some embodiments lowerdrug levels will be sufficient). In a preferred embodiment, mitoxantroneis released from the intraocular lens surface such that anti-infectiveactivity is maintained for a period ranging from several hours toseveral months. In a particularly preferred embodiment the drug isreleased in effective concentrations for a period ranging from 1-12weeks. It should be readily evident based upon the discussion providedherein that analogues and derivatives of mitoxantrone (as describedpreviously) with similar functional activity can be utilized for thepurposes of this invention; the above dosing parameters are thenadjusted according to the relative potency of the analogue or derivativeas compared to the parent compound (e.g. a compound twice as potent asmitoxantrone is administered at half the above parameters, a compoundhalf as potent as mitoxantrone is administered at twice the aboveparameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5-fluorouracil asan example, whether applied as a polymer coating, incorporated into thepolymers which make up the intraocular lens, or applied without acarrier polymer, the total dose of 5-fluorouracil applied should notexceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of10 μg to 25 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the intraocular lens towhich drug is applied and/or incorporated) should fall within the rangeof 0.1 μg-1 mg per mm² of surface area. In a particularly preferredembodiment, 5-fluorouracil should be applied to the intraocular lenssurface at a dose of 1.0 μg/mm²-50 μg/mm². As different polymer andnon-polymer coatings will release 5-fluorouracil at differing rates, theabove dosing parameters should be utilized in combination with therelease rate of the drug from the intraocular lens surface such that aminimum concentration of 10⁻⁴-10⁻⁷ M of 5-fluorouracil is maintained. Itis necessary to insure that surface drug concentrations exceedconcentrations of 5-fluorouracil known to be lethal to numerous speciesof bacteria and fungi (i.e., are in excess of 10⁻⁴ M; although for someembodiments lower drug levels will be sufficient). In a preferredembodiment, 5-fluorouracil is released from the intraocular lens surfacesuch that anti-infective activity is maintained for a period rangingfrom several hours to several months. In a particularly preferredembodiment the drug is released in effective concentrations for a periodranging from 1-12 weeks. It should be readily evident based upon thediscussion provided herein that analogues and derivatives of5-fluorouracil (as described previously) with similar functionalactivity can be utilized for the purposes of this invention; the abovedosing parameters are then adjusted according to the relative potency ofthe analogue or derivative as compared to the parent compound (e.g. acompound twice as potent as 5-fluorouracil is administered at half theabove parameters, a compound half as potent as 5-fluorouracil isadministered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as anexample, whether applied as a polymer coating, incorporated into thepolymers which make up the intraocular lens, or applied without acarrier polymer, the total dose of etoposide applied should not exceed25 mg (range of 0.1 μg to 25 mg). In a particularly preferredembodiment, the total amount of drug applied should be in the range of 1μg to 5 mg. The dose per unit area (i.e. the amount of drug as afunction of the surface area of the portion of the intraocular lens towhich drug is applied and/or incorporated) should fall within the rangeof 0.01 μg-100 μg per mm² of surface area. In a particularly preferredembodiment, etoposide should be applied to the intraocular lens surfaceat a dose of 0.1 μg/mm²-10 μg/mm². As different polymer and non-polymercoatings will release etoposide at differing rates, the above dosingparameters should be utilized in combination with the release rate ofthe drug from the intraocular lens surface such that a concentration of10⁻⁵-10⁻⁶ M of etoposide is maintained. It is necessary to insure thatsurface drug concentrations exceed concentrations of etoposide known tobe lethal to a variety of bacteria and fungi (i.e. are in excess of 10⁻⁵M; although for some embodiments lower drug levels will be sufficient).In a preferred embodiment, etoposide is released from the surface of theintraocular lens such that anti-infective activity is maintained for aperiod ranging from several hours to several months. In a particularlypreferred embodiment the drug is released in effective concentrationsfor a period ranging from 1-12 weeks. It should be readily evident basedupon the discussion provided herein that analogues and derivatives ofetoposide (as described previously) with similar functional activity canbe utilized for the purposes of this invention; the above dosingparameters are then adjusted according to the relative potency of theanalogue or derivative as compared to the parent compound (e.g. acompound twice as potent as etoposide is administered at half the aboveparameters, a compound half as potent as etoposide is administered attwice the above parameters, etc.).

(d) Combination therapy. It should be readily evident based upon thediscussions provided herein that combinations of anthracyclines (e.g.,doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil),folic acid antagonists (e.g., methotrexate) and podophylotoxins (e.g.,etoposide) can be utilized to enhance the antibacterial activity of theintraocular lens coating. Similarly anthracyclines (e.g., doxorubicin ormitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acidantagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,etoposide) can be combined with traditional antibiotic and/or antifungalagents to enhance efficacy.

Corneal Infections Secondary to Contact Lens Use

Contact lenses are primarily used for the correction of refractiveerrors, but are also used after cataract surgery (Aphakie lenses) and“bandage” lenses are used following corneal trauma. Over 24 millionpeople wear contact lenses and many of them will suffer from ulcerativekeratitis resulting from contact lens-associated infection. Theseinfections are typically bacterial in nature, are secondary to cornealdamage/defects, and are caused primarily by Gram Positive Cocci andPseudomonas aeruginosa.

The drug-coating of contact lenses is identical to the embodimentdescribed above for intraocular lenses. In addition, doxorubicin,mitoxantrone, 5-fluorouracil and/or etoposide can be added to contactlens storage solution to prevent infection transmitted via infectedcleaning/storage solutions.

It should be readily evident to one of skill in the art that any of thepreviously mentioned agents, or derivatives and analogues thereof, canbe utilized to create variation of the above compositions withoutdeviating from the spirit and scope of the invention.

EXAMPLES Example 1 MIC Determination by Microtitre Broth Dilution Method

A. MIC assay of various gram negative and positive bacteria MIC assayswere conducted essentially as described by Amsterdam, D. 1996.Susceptibility testing of antimicrobials in liquid media, p. 52-111. InLoman, V., ed. Antibiotics in laboratory medicine, 4th ed. Williams andWilkins, Baltimore, Md. Briefly, a variety of compounds were tested forantibacterial activity against isolates of P. aeruginosa, K. pneumoniae,E. coli, S. epidermidus and S. aureus in the MIC (minimum inhibitoryconcentration assay under aerobic conditions using 96 well polystyrenemicrotitre plates (Falcon 1177), and Mueller Hinton broth at 37° C.incubated for 24 h. (MHB was used for most testing except C721 (S.pyogenes), which used Todd Hewitt broth, and Haemophilus influenzae,which used Haemophilus test medium (HTM)) Tests were conducted intriplicate. The results are provided below in Table 1. TABLE 1 MinimumInhibitory Concentrations of Therapeutic Agents Against Various GramNegative and Positive Bacteria Bactrial Strain P. aeruginosa K.pneumoniae E. coli S. aureus PAE/K799 ATCC13883 UB1005 ATCC25923 S.epidermidis S. pyogenes H187 Wt C238 wt C498 wt C622 wt C621 wt C721 wtDrug Gram− Gram− Gram− Gram+ Gram+ Gram+ doxorubicin 10⁻⁵ 10⁻⁶ 10⁻⁴ 10⁻⁵10⁻⁶ 10⁻⁷ mitoxantrone 10⁻⁵ 10⁻⁶ 10⁻⁵ 10⁻⁵ 10⁻⁵ 10⁻⁶ 5-fluorouracil 10⁻⁵10⁻⁶ 10⁻⁶ 10⁻⁷ 10⁻⁷ 10⁻⁴ methotrexate N 10⁻⁶ N 10⁻⁵ N 10⁻⁶ etoposide N10⁻⁵ N 10⁻⁵ 10⁻⁶ 10⁻⁵ camptothecin N N N N 10⁻⁴ N hydroxyurea 10⁻⁴ N N NN 10⁻⁴ cisplatin 10⁻⁴ N N N N N tubercidin N N N N N N 2-mercaptopurineN N N N N N 6-mercaptopurine N N N N N N Cytarabine N N N N N NActivities are in Molar concentrationsWt = wild typeN = No activity

B. MIC of Antibiotic-Resistant Bacteria

Various concentrations of the following compounds, mitoxantrone,cisplatin, tubercidin, methotrexate, 5-fluorouracil, etoposide,2-mercaptopurine, doxorubicin, 6-mercaptopurine, camptothecin,hydroxyurea and cytarabine were tested for antibacterial activityagainst clinical isolates of a methicillin resistant S. aureus and avancomycin resistant pediocoocus clinical isolate in an MIC assay asdescribed above. Compounds which showed inhibition of growth (MIC valueof <1.0×10−3) included: mitoxantrone (both strains), methotrexate(vancomycin resistant pediococcus), 5-fluorouracil (both strains),etoposide (both strains), and 2-mercaptopurine (vancomycin resistantpediococcus).

Example 2 Catheter Dip Coating—Non-Degradable Polymer

A coating solution is prepared by dissolving 20 g ChronoFlex AI 85A (CTBiomaterials) in 100 mL DMAC:THF (40:60) at 50° C. with stirring. Oncedissolved, the polymer solution is cooled to room temperature. 20 mgmitoxantrone is added to 2 mL of the polyurethane solution. The solutionis stirred until a homogenious mixture is obtained. Polyurethane 7French tubing is dipped into the polymer/drug solution and thenwithdrawn. The coated tube is air dried (80° C.). The sample is thendried under vacuum to further reduce the residual solvent in thecoating.

Example 3 Catheter Dip Coating—Degradable Polymer

A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mLdichloromethane:methanol (70:30). Once dissolved, 20 mg mitoxantrone isadded to the polymer solution. Once the solution is a homogeneoussolution, polyurethane 7 French tubing is dipped into the solution andthen withdrawn. The coated tube is air dried. The sample is then driedunder vacuum to further reduce the residual solvent in the coating.

Example 4 Catheter Dip Coating—Drug Only

1 mL methanol is added to 20 mg mitoxantrone. Polyurethane 7 Frenchtubing is dipped into the solution and then withdrawn. The coated tubeis air dried. The sample is then dried under vacuum to further reducethe residual solvent in the coating.

Example 5 Catheter Dip Coating—Drug Impregnation

0.6 mL methanol is added to 20 mg mitoxantrone. 1.4 mL DMAC is addedslowly. Polyurethane 7 French tubing is dipped into the solution. Aftervarious periods of time (2 min, 5 min, 10 min, 20 min, 30 min) the tubewas withdrawn. The coated tube is air dried (80° C.). The sample is thendried under vacuum to further reduce the residual solvent in thecoating.

Example 6 Tympanostomy Tubes Dip Coating—Non-Degradable Polymer

A coating solution is prepared by dissolving 20 g ChronoFlex AI 85A (CTBiomaterials) in 100 mL DMAC:THF (50:50) at 50° C. with stirring. Oncedissolved, the polymer solution is cooled to room temperature. 20 mgmitoxantrone is added to 2 mL of the polyurethane solution. The solutionis stirred until a homogenious mixture is obtained. A stainless steeltympanostomy tube is dipped into the polymer/drug solution and thenwithdrawn. The coated tube is air dried (80° C.). The sample is thendried under vacuum to further reduce the residual solvent in thecoating.

Example 7 Catheter Dip Coating—Non-Degradable Polymer

A coating solution is prepared by dissolving 20 g ChronoFlex AI 85A (CTBiomaterials) in 100 mL THF at 50° C. with stirring. Once dissolved, thepolymer solution is cooled to room temperature. 20 mg etoposide is addedto 2 mL of the polyurethane solution. The solution is stirred until ahomogenious mixture is obtained. Polyurethane 7 French tubing is dippedinto the polymer/drug solution and then withdrawn. The coated tube isair dried (80 C). The sample is then dried under vacuum to furtherreduce the residual solvent in the coating.

Example 8 Catheter Dip Coating—Degradable Polymer

A coating solution is prepared by dissolving 2 g PLG (50:50) in 10 mLdichloromethane:methanol (70:30). Once dissolved, 20 mg etoposide isadded to the polymer solution. Once the solution is a homogeneoussolution, polyurethane 7 French tubing is dipped into the solution andthen withdrawn. The coated tube is air dried. The sample is then driedunder vacuum to further reduce the residual solvent in the coating.

Example 9 Catheter Dip Coating—Drug Only

1 mL THF is added to 20 mg etoposide. Polyurethane 7 French tubing isdipped into the solution and then withdrawn. The coated tube is airdried. The sample is then dried under vacuum to further reduce theresidual solvent in the coating.

Example 10 Catheter Dip Coating—Drug Impregnation

0.6 mL methanol is added to 1.4 mL DMAC which contains 20 mg etoposide.Polyurethane 7 French tubing is dipped into the solution. After variousperiods of time (2 min, 5 min, 10 min, 20 min, 30 min) the tube waswithdrawn. The coated tube is air dried (80° C.). The sample is thendried under vacuum to further reduce the residual solvent in thecoating.

Example 11 Tympanostomy Tubes Dip Coating—Non-Degradable Polymer

A coating solution is prepared by dissolving 20 g ChronoFlex AI 85A (CTBiomaterials) in 100 mL DMAC:THF (50:50) at 50° C. with stirring. Oncedissolved, the polymer solution is cooled to room temperature. 20 mgetoposide is added to 2 mL of the polyurethane solution. The solution isstirred until a homogenious mixture is obtained. A stainless steeltympanostomy tube is dipped into the polymer/drug solution and thenwithdrawn. The coated tube is air dried (80° C.). The sample is thendried under vacuum to further reduce the residual solvent in thecoating.

Example 12 Covalent Attachment of Doxorubicin to a Polymer Coated Device

A piece of polyurethane 7 French tubing, with and without an oxygenplasma pretreatment step, is dipped into a solution of 5% (w/w)poly(ethylene-co acrylic acid) in THF. The sample was dried at 45° C.for 3 hours. The coated tubing was then dipped into a water:methanol(30:70) solution that contained1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mLDoxorubicin. After various times (15 min, 30 min, 60 min 120 min) thetubing is removed from the solution and dried at 60° C. for 2 hoursfollowed by vacuum drying for 24 hours.

Example 13 Covalent Attachment of Doxorubicin to a Device Surface

A piece of polyurethane 7 French tubing that has undergone a oxygenplasma pretreatment step is dipped into a water:methanol (30:70)solution that contained 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) and 20 mg/mL Doxorubicin. After various times (15 min, 30 min, 60min 120 min) the tubing is removed from the solution and dried at 60° C.for 2 hours followed by vacuum drying for 24 hours.

Example 14 Impregnation of 5-Fluorouracil into Polyurethane Catheter

A solution was prepared by dissolving 100 mg of 5-Fluorouracil into 20ml anhydrous methanol. Polyurethane catheter tubing was immersed in thissolution for 16 hours. The catheter tubing was vacuum dried at 50° C.for 16 hours.

Example 15 Impregnation of Mitoxantrone into Polyurethane Catheter

A solution was prepared by dissolving 20 mg of Mitoxantrone-2HCl into 20ml anhydrous methanol. Polyurethane catheter tubing was immersed in thissolution for 16 hours. The catheter tubing was vacuum dried at 50° C.for 16 hours.

Example 16 Impregnation of Doxorubicin into Polyurethane Catheter

A solution was prepared by dissolving 20 mg of Doxorubicin-HCl into 20ml anhydrous methanol. Polyurethane catheter tubing was immersed in thissolution for 16 hours. The catheter tubing was vacuum dried at 50° C.for 16 hours.

Example 17 Polyurethane Dip Coating with 5-Fluorouracil

A solution was prepared by dissolving 125 mg 5-Fluorouracil and 2.5 g ofChronoflex AL85A (CT Biomaterials) in 50 ml of THF at 55° C. Thesolution was cooled to room temperature. Polyurethane catheters wereweighted at one end and dipped in solution and then removed immediately.This process was repeated three times with 1 minute drying time intervalbetween each dipping process. The catheter tubing was vacuum dried at50° C. for 16 hours.

Example 18 Polyurethane Dip Coating with 5-Fluorouracil and PalmiticAcid

A solution was prepared by dissolving 125 mg 5-Fluorouracil, 62.5 mg ofpalmitic acid, and 2.437 g of Chronoflex AL85A (CT Biomaterials) in 50ml of THF at 55° C. The solution was cooled to room temperature.Polyurethane catheters were weighted at one end and dipped in solutionand then removed immediately. This process was repeated three times witha 1 minute drying time interval between each dipping process. Thecatheter tubing was vacuum dried at 50° C. for 16 hours.

Example 19 Catheter Dip Coating with Nafion and Mitoxantrone

Catheters are weighted at one end and dipped into 5% Nafion solution(Dupont) and then removed immediately. This process was repeated threetimes with a 1 minute drying time interval between each dipping process.The catheter tubing was dried at room temperature for 2 hours. Asolution was prepared with 1 mg of mitoxantrone-2HCl in 40 ml ofdeionized water. The catheter tubing was immersed in the solution for 5minutes, and then was washed with deionized water and dried at roomtemperature.

Example 20 Catheter Dip Coating with Nafion and Doxorubicin

Catheters are weighted at one end and dipped into 5% Nafion solution(Dupont) and then removed immediately. This process was repeated threetimes with a 1 minute drying time interval between each dipping process.The catheter tubing was dried at room temperature for 2 hours. Asolution was prepared with 1 mg of doxorubicin-HCl in 40 ml of deionizedwater. The catheter tubing was immersed in the solution for 5 minutes,and then was washed with deionized water and dried at room temperature.

Example 21 Preparation of Release Buffer

The release buffer was prepared by adding 8.22 g sodium chloride, 0.32 gsodium phosphate monobasic (monohydrate) and 2.60 g sodium phosphatedibasic (anhydrous) to a beaker. 1 L HPLC grade water was added and thesolution was stirred until all the salts were dissolved. If required,the pH of the solution was adjusted to pH 7.4±0.2 using either 0.1N NaOHor 0.1N phosphoric acid.

Example 22 Release Study to Determine Release Profile of the TherapeuticAgent from a Catheter

A sample of the therapeutic agent-loaded catheter was placed in a 15 mLculture tube. 15 mL release buffer (Example 21) was added to the culturetube. The tube was sealed with a Teflon lined screw cap and was placedon a rotating wheel in a 37° C. oven. At various time point, the bufferis withdrawn from the culture tube and is replaced with fresh buffer.The withdrawn buffer is then analysed for the amount of therapeuticagent contained in this buffer solution.

Example 23 HPLC Analysis of Therapeutic Agents in Release Buffer

The following chromatographic conditions were used to quantify theamount of the therapeutic agent in the release medium: Flow RunInjection Detection Therapeutic Rate Time Volume Wavelength Agent ColumnMobile Phase (mL/min) (min) (uL) (nm) 5-Fluorouracil YMC ODS-AQ 150 ×4.6 mm, 5 um PBS, pH 6.8 1 8 100 268 Doxorubicin ACE 5 (V02-742) 150 × 4mm 20% CAN, 26% Methanol, 1 10 10 254 54% PBS (pH 3.6) Mitoxantrone ACE5 C18, 150 × 4 mm, 5 um Phosphate buffer (pH 2.3) 1 4 10 658

Example 24 Effect of Palmitic Acid on the Release Profile of5-Fluorouracil from a Polyurethane Film

A 25% (w/v) Chronoflex AL 85A (CT Biomaterials) solution was prepared inTHF. 50 mg 5-fluorouracil was weighed into each of 4 glass scintillationvials. Various amount of palmitic acid were added to each vial. 20 mL ofthe polyurethane solution was added to each scintillation vial. Thesamples were rotated at 37° C. until the solids had all dissolved.Samples were then cast as films using a casting knife on a piece ofrelease liner. Samples were air dried and then dried overnight undervacuum. A portion of these samples were used to perform release studies(Example 22). FIG. 1 show the effect of palmitic acid on the releaseprofile of 5-fluorouracil.

Example 25 Radial Diffusion Assay for Testing Drug Impregnated CathetersAgainst Various Strains of Bacteria

An overnight bacterial culture was diluted 1 to 5 to a final volume of 5mls fresh Mueller Hinton broth. Then 100 μl of the diluted bacterialculture were spread onto Mueller Hinton agar plates. A test material(e.g., catheter tubing), with or without drug, was placed on the centerof the plate. For example, catheters are typically 1 cm long and about 3mm in diameter (which may be made of polyurethane, silicon or othersuitable material) and are loaded with drug either through dip-coatingor through use of a drug-impregnated coating. The plates were incubatedat 37° C. for 16-18 hours. The zone of clearing around a test materialwas then measured (e.g., the distance from the catheter to wherebacterial growth is inhibited), which indicated the degree of bacterialgrowth prevention. Various bacterial strains that may be tested include,but are not limited to, the following: E. coli C498 UB1005, P.aeruginosa H187, S. aureus C622 ATCC 25923, and S. epidermidis C621.

One cm polyurethane catheters coated with 5-fluorouracil at severalconcentrations (2.5 mg/mL and 5.0 mg/mL) were examined for their effectagainst S. aureus. The zone of inhibition around the catheters coated ina solution of 2.5 mg/mL 5-Fluorouracil and placed on Mueller Hinton agarplates as described above was 35×39 mm, and for the catheters coated ina solution of 5.0 mg/mL 5-Fluorouracil was 30×37 mm. Catheters withoutdrug showed no zone of inhibition. These results demonstrate theefficacy of 5-fluorouracil coated on a catheter at inhibiting the growthof S. aureus.

From the foregoing, it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1.-18. (canceled)
 19. A method for reducing or inhibiting infectionassociated with a medical implant, comprising the step of introducinginto a patient a medical implant which has been covered or coated withan anthracycline, fluoropyrimidine, folic acid antagonist,podophylotoxin, camptothecin, hydroxyurea, or platinum complex.
 20. Themethod according to claim 19 wherein said fluoropyrimidine is5-fluorouracil. 21.-23. (canceled)